Stereoselective synthesis of endothelin receptor antagonists

ABSTRACT

The present invention is directed to chiral intermediates in a synthetic route for preparing endothelium receptor antagonists of formulae (7B) and (7A). ##STR1##

This is a divisional of application Ser. No. 09/068,427, filed May 8,1998; now U.S. Pat. No. 6,080,862; which is a 371 of InternationalApplication PCT/US96/18084. filed Nov. 08, 1996; which claims thebenefit of priority of Provisional Application Ser. No. 60/006,348,filed Nov. 08, 1995 and Ser. No. 60/006,347 filed Nov. 08, 1995.

FIELD OF THE INVENTION

The present invention relates to the stereoselective synthesis of aryland heteroaryl ring-fused cyclopentane derivatives useful as endothelinreceptor antagonists and to the preparation of chiral intermediates inthe process.

BACKGROUND OF THE INVENTION

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesizedand released by the vascular endothelium. Endothelin exists as threeisoforms, ET-1, ET-2 and ET-3 (unless otherwise stated, "endothelin"shall mean any or all of the isoforms of endothelin). Endothelin hasprofound effects on the cardiovascular system, and in particular, thecoronary, renal and cerebral circulation. Elevated or abnormal releaseof endothelin is associated with smooth muscle contraction which isinvolved in the pathogenesis of cardiovascular, cerebrovascular,respiratory and renal pathophysiology. Elevated levels of endothelinhave been reported in plasma from patients with essential hypertension,acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis,and patients with uraemia undergoing dialysis.

Many studies suggest that endothelin receptor antagonists would offer aunique approach toward the pharmacotheraphy of hypertension, renalfailure, ischemia-induced renal failure, sepsis-endotoxin-induced-renalfailure, prophylaxis and/or treatment of radio-contrast-induced renalfailure, acute and chronic cyclosporin-induced renal failure,cerebrovascular disease, myocardial ischemia, angina, heart failure,asthma, pulmonary hypertension, pulmonary hypertension secondary tointrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon,ulcers, sepsis, migraine, glaucoma, endotoxin shock endotoxin-inducedmultiple organ failure or disseminated intravascular coagulation,cyclosporin induced renal failure and as an adjunct in angioplasty forprevention of restenosis, diabetes, preclampsia of pregnancy, boneremodeling, kidney transplant, male contraceptives, infertility andpriaprism and benign prostatic hypertrophy.

Recent publications disclose that aryl and heteroaryl ring-fusedcyclopentane derivatives have utility as endothelin receptorantagonists. See, e.g., International application Number PCT/US94/04603(WO 94/25013) and U.S. Pat. No. 5,389,620. These particular publicationsalso disclose synthetic approaches to the preparation of specific aryland heteroaryl ring-fused cyclopentane derivatives, where thosederivatives may function as endothelin receptor antagonists.

Unfortunately, the synthetic methods disclosed in the literature formaking aryl and heteroaryl ring-fused cyclopentane derivatives do notprovide for the desired products in high yield. Instead, the methodsdiscussed in the literature require many steps, which are laborious andconsequently expensive to conduct. Furthermore, when known methodsprovide for enantiomerically or diastereomerically pure products, theyrely on chromatography to separate the various stereoisomers.Chromatography is far from a preferred approach in the preparation ofisomerically pure materials on a commercial scale. Exemplary of thisapproach is the synthesis of (+) (1S,2R,3S)3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and (+) (1S,2R,3S)3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid, which asset forth in WO 94/25013, is multi-step, low yielding and relies upon achromatographic resolution of a racemic intermediate in order to preparethe named compounds in optically pure form.

A technique that needs to be developed in the synthetic art is the useof chiral aryl Grignard reagents. Chiral aryl Grignard reagents haveseen some use as intermediates for the preparation of diastereomericallyand enantiomerically pure compounds. Such chiral aryl Grignard reagentshave been prepared, for example, from chiral oxazolidines derived fromaryl aldehydes. See, e.g., Real, S. D. et al., U.S. Pat. No. 5,332,840and Tet. Lett., 34, 8063-8066, 1993; Agami, C. et al., Tetrahedron, 41,537-540, 1985; and Takahashi, H. et al., Synthesis, 681-682, 1992.Depending upon the reaction conditions, good to excellentdiastereoselectivity has been reported for the addition of such chiralGrignard species to aldehydes, ketones and anhydrides. Aryl aldehydeshave also been converted to chiral aryl Grignard reagents throughformation of a homochiral acetal group adjacent to the Grignard reactivesite. Such chiral materials have also been utilized indiastereoselective additions to carbonyl groups. See, e.g., Yamamoto, H.et al., Bull. Chem. Soc. Jpn., 62, 3736-3738, 1989.

However, the utility of chiral aryl Grignard reagents derived fromchiral aryl ethers, wherein a phenol has been protected with a suitablechiral protecting group has seen little, if any, practical application.In one example where a chiral aryl Grignard reagent was derived from achiral aryl ether, and then reacted with a carbonyl compound, only aslight diastereoselectivity for the reaction might be inferred, but wasnot conclusively established. See Ronald et al., J. Org. Chem., 45,2224-2229, 1980.

Thus, the preparation of chiral aryl Grignard reagents derived fromchiral aryl ethers, and their use in the preparation ofdiastereomerically and enantiomerically pure compounds in the synthesisof aryl and heteroaryl ring fused cyclopentane derivatives, has not yetbeen established as viable synthetic methodology. Such methodology hasutility in, for example, the preparation of endothelin receptorantagonists as disclosed in WO/9308799-A1 and U.S. Pat. No. 5,389,620,both of which are incorporated by reference herein, which to date havebeen prepared only via racemic mixtures of compounds, where chiralchromatography is necessary to obtain enantiomerically pure compounds.See, e.g., WO/9308799-A 1. There is thus a need in the art to exploitchiral aryl Grignard reagents in the synthetic methodology useful in thepreparation of enantiomerically and diastereomerically pure compoundsthat may be converted to endothelin receptor antagonists, and where thecompounds are in enantiomerically or diastereomerically pure formwithout the need to resort to time-consuming and expensivechromatography.

Moreover, as explained more fully below, a preferred stereoselectivesynthesis of aryl and heteroaryl ring-fused cyclopentane derivativeswill be able to place substituents at the three contiguous, non-ringfused carbons of the cyclopentane ring in a stereocontrolled manner.Furthermore, a preferred synthetic method will proceed in high overallyield, with minimal need to isolate and purify intermediates. This is asophisticated challenge which is not met by any currently recognizedsynthetic methods.

There is thus a need in the art for an efficient synthetic method toprepare aryl and heteroaryl ring-fused cyclopentane derivatives, incompletely or substantially enantiomerically or diastereomerically pureform, without the need to resort to chromatographic purification. Inparticular, there is a need in the art for methods to prepare (+)(1S,2R,3S)3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and (+) (1S,2R,3S)3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid, and pharmaceutically acceptable salts thereof, in an efficient andeconomical manner.

The numerous advantages of the presently invented processes andintermediates will become apparent upon review of the followingdescription.

SUMMARY OF THE INVENTION

The present invention is directed to a process for preparing aryl andheteroaryl ring fused cyclopentane derivatives of the formula: ##STR2##or pharmaceutically acceptable salts thereof wherein

R₃ ', R₄ ' and R₅ ' are independently hydrogen, C₁ -C₆ alkyl, C₁ -C₈alkoxy, or hydroxy;

R₁₂ ' is (CH₂)₂ OH or (CH₂)p CO₂ H;

p is an integer 1-3;

A, B, G and D are each carbon atoms or one of A, B, G and D is anitrogen atom, and the remainder are carbon atoms;

Z' is hydrogen, hydroxy, C₁ -C₅ alkoxy or C₁ -C₅ alkyl; and

R₁₁ ' is unsubstituted 3,4-methylenedioxyphenyl or substituted 3,4methylenedioxyphenyl, wherein the substituent is on the phenyl ring andis C₁ -C₅ alkyl, C₁ -C₅ alkoxy or hydroxy.

These compounds of Formulae 7A and 7B are useful as endothelin receptorantagonists. Examples of compounds useful is endothelin receptorantagonists that fall within the purview of these formula include(+)-(1S, 2R, 3S)-3-(2-carboxymethoxy-2methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylicacid and (+)-(1S, 2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylicacid. As described hereinbelow, both compounds of Formula 7A and 7B areprepared by analogous processes. An examplary procedure for thepreparation of compound 7A is depicted in Schemes 1-4, but the scheme isequally applicable for the preparation of a compound of Formula 7B.

In Scheme 1, an ortho-halo phenolic compound of Formula (1) wherein R₁is halide, is reacted with a chiral electrophile of Formula (2)designated "R₂ L" wherein "L" is a leaving group. This reaction affordsan aryl ether where the phenolic group is protected by a chiralauxiliary (R₂) ortho to the halide (R₁) on a benzene ring, asrepresented by Formula (3). In the next step, the aryl halide of Formula(3) is converted to a reactive organometallic intermediate which in turnis reacted with a cyclopentenone of Formula (4) to provide a mixture ofdiastereomeric carbinols having Formulas (5A) and (5B). One of thecarbinols (5A) or (5B), denoted the predominant diastereomer, willtypically be formed in diastereomeric excess due to the influence of thechiral auxiliary (R₂). In a final step of Scheme 1, the mixture ofdiastereomeric carbinols may be subjected to a crystallization processto provide the predominant isomer in essentially pure form.

The diastereomerically-related compounds (5A) and (5B) as shown inScheme 2, are stereoselectively hydrogenated to afford a compositioncomprising diastereomerically-related compounds (6A) and (6B). Themixture of compounds of Formulae (6A) and (6B) may optionally besubjected to a crystallization process in order to provide a single oneof the diastereomers in essentially pure form.

6A is utilized to prepare 7A by two different processes, as shown inScheme 3. According to Route (B) in Scheme 3, and exemplified more fullyin Scheme 4, a diastereomerically pure compound of Formula (6A) isconverted to a compound of Formula (13A) via a compound of Formula (11A)by hydrolysis and epimerization of the carboxylate ester at C2 followedby cleavage of the chiral aryl ether component and re-esterification ofthe carboxylate group at C2. A compound of Formula (13A) is thenalkylated to afford an enantiomerically pure compound of Formula (14A)which is saponified to afford enantiomerically pure endothelin receptorantagonists of Formula (7A).

Alternatively, according to Route (A) chemistry in Scheme 3, adiastereomerically pure compound of Formula (6A) is converted to acompound of Formula (8A) by cleavage of the chiral aryl ether OR₂ group.Compounds of Formula (8A) are then alkylated to afford enantiomericallypure compounds of Formula (9A) which is then saponified to affordenantiomerically pure endothelin receptor antagonists of Formula (7A).

In the formulae in the various schemes, R₃, R₄ and R₅ are independentlyhydrogen, C₁ -C₆ alkyl, C₁ -C₈ alkoxy, halide or protected hydroxy;

R₁ is halide, especically bromide, chloride, or iodide;

R₂ is selected from the group consisting of anomers, enantiomers, anddiestereomers of (1) carbohydrates and derivatives thereof, (2) terpenesand derivatives thereof and (3) amino acids and derivatives thereof,

L is a leaving group;

A, B, G and D are independently carbon atoms or one of A, B, G and D isa nitrogen atom and the remainder are a carbon atoms;

Z is hydrogen, protected hydroxy, C₁ -C₅ alkoxy or C₁ -C₅ alkyl;

R₁₁ is unsubstituted 3,4-methylenedioxyphenyl or substituted3,4-methylene-dioxyphenyl wherein the substituent is on the phenyl ringand is C₁ -C₅ alkyl, C₁ -C₅ alkoxy or protected hydroxy;

R₁₀ is C₁ -C₅ alkyl;

R₁₂ is (CH₂)₂ OH or (CH₂)p CO₂ R₁₃ ;

R₁₃ is C₁ -C₅ alkyl or hydrogen; and

p is an integer from 1 to 3.

Another aspect of the present invention is directed to synthetic methodsuseful in preparing novel intermediates, such as, for example compounds3, 5A, 5B, 6A, 6B, 8A, 8B, 9A, 9B, 11A, 11B, 13A, 13B and 14A, and 14Bidentified hereinbelow.

A particularly preferred aspect of the invention is directed tosynthetic methods useful in preparing novel intermediates that may beconverted to (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof.

Another aspect of the present invention is directed to the novelintermediates useful in the preparation of the compounds of Formulae 7Aand 7B. ##STR3##

DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless designated to the contrary, the term alkyl,when used alone or in combination, refers to an alkyl group which may bestraight chained or branched. Preferred alkyl groups contain 1-8 carbonatoms, and even more preferred alkyl groups contain 1-6 carbon atoms. Itis even more preferred that the alkyl group contains 1-3 carbon atoms,with methyl being the most preferred. Examples include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl,amyl, hexyl and the like.

The term alkoxy, when used alone or in combination, refers to o-alkyl.The preferred alkoxy group contains 1-3 carbon atoms.

The term halide refers to fluoride, bromide, chloride, or iodide, withbromide and chloride being the most preferred halides.

The term "protected hydroxyl" as used herein and throughout thisspecification means hydroxyl groups that have been reacted withappropriate protecting groups, where appropriate protecting groups forhydroxyl groups are well known in the art. Protecting groups which canbe utilized are described in Greene, "Protecting Groups in OrganicSynthesis", 1991, John Wiley and Sons, Inc., the contents of which areincorporated herein by reference. For example, in the case of simplephenolic hydroxyls, a suitable method of protection is thetransformation of the hydroxyl groups to an aryl ether, e.g., methylether, methoxymethyl ether, benzyloxy methyl ether or cyclopropyl methylether. In the case of catechols (dihydroxy benzene), suitable protectionthereof may be as a cyclic ether, for example, as a methylene acetal, anacetonide derivative or cyclohexylidene ketal.

The preferred R₁ groups are iodo, and especially bromo and chloro.

The preferred R₃, R₄ and R₅ as well as R₃ ', R₄ ' and R₅ ' groups areindependently hydrogen, C₁ -C₆ alkyl, or C₁ -C₈ alkoxy. It is morepreferred that R₃, R₄ and R₅ and R₃ ', R₄ ' and R₅ ' are independentlyhydrogen or C₁ -C₈ alkoxy. It is even more preferred that R₃ and R₅ andR₃ ' and R₅ ' are hydrogen and R₄ and R₄ ' are alkoxy, as definedherein, especially methoxy. Furthermore, it is preferred that R₄ and R₄' are each para to R₁ and R₁ ', respectively and it is most preferredthat R₄ is alkoxy and is para to R₁ and that R₄ ' is alkoxy and para toR₁ '.

The preferred values of L are halide, especially chlorides, iodides andbromides, tosylates, and mesylates.

As defined herein, A, B, G and D, are either all carbon atoms or one ofthem is a nitrogen atom. If one is a nitrogen atom, it is preferred thatthe nitrogen atom be present in the one-position, i.e., it is preferredthat D be a nitrogen atom. However, it is more preferred that A, B, Gand D are all carbon atoms.

The ring containing A, B, G and D may either be substituted orunsubstituted. It is preferred that the ring is substituted. Thepreferred values of Z and Z'are lower alkyl or lower alkoxy, andespecially preferred values of Z and Z' are lower alkoxy. Moreover, itis preferred that Z and Z' are substituted on B.

The preferred R₁₁ substituent is unsubstituted 3,4-methylenedioxyphenyl.

The preferred value of p is 1 or 2.

The preferred values of the other substituents will be discussed, infra.

In comparing the formulae of 7A (or 7B) with the other structureshereinabove, it is noted that R₃ and R₃ ', R₄ and R₄ ', R₅ and R₅ ', Zand Z₁ ', and R₁₁ and R₁₁ ' each have similar definition. Except whenR₃, R₄, R₅, R₁₁ and Z are a protected hydroxy, the definitions of R₃,R₄, R₅, R₁₁ and Z are the same as R₃ ', R₄ ', R₅ ', R₁₁ ' and Z₁ 'respectively. It is noted that during the reaction conditions describedherein, the hydroxy group if left unprotected, will be reactive.However, in the final product, 7A or 7B, the hydroxy group is no longerrequired to be protected. Thus, if the OH group are protected, it ispreferred that at the end of the sequence of reactions, the protectinggroup be removed. Techniques for removing hydroxy protecting groups arewell known in the art and are described in, e.g., Greene referred tohereinabove.

R₁₂ and R₁₂ ' also have similar definitions. Both R₁₂ and R₁₂ ' are(CH₂)₂ OH. However, R₁₂ may also be (CH₂)p COOH. In other words, R₁₂ mayalso be an ester substituent, which, as described hereinbelow, ishydrolyzed to form the corresponding acid, i.e., R₁₂ '.

Consequently, there is a relationship between the values R₃ -R₅, and R₃'-R₅ ', Z and Z', R₁₁ and R₁₁ ' and R₁₂ and R₁₂ '. For example, if R₃,R₄, R₅ or Z is a protected hydroxy, then the corresponding value of R₃', R₄ ', R₅ ' and Z₁ ', respectively is hydroxy; on the other hand, ifR₃, R₄ or R₅, or Z is other than protected hydroxy, then each of R₃, R₄,R₅ and Z have the same value as the corresponding R₃ ', R₄ ', R₅ ' andZ₁ '. Moreover, if R₁₁ contains a protected hydroxy substituent, thenR₁₁ ' contains a hydroxy substituent; on the other hand, if R₁₁ isdifferent than protected hydroxy, then R₁₁ and R₁₁ ' are the same.Finally, if R₁₂ is (CH₂)₂ OH, then R₁₂ ' is (CH₂)₂ OH; however, if R₁₂is (CH₂)pCO₂ R₁₃, then R₁₂ ' has the corresponding value (CH₂)pCOOH.

The compounds 7A and 7B are synthesized in accordance with the presentinvention, as described hereinbelow.

As described herein, the ortho-halo phenolic compounds of Formula Ihereinbelow are useful precursors in the inventive methodology of thepresent invention. In Formula (1), R₁ is chloride, bromide or iodide,and is bonded to a benzene ring. A hydroxy group is located in an orthoposition to R₁. Thus, the compounds of Formula (1) may be denoted asortho-halo phenolic compounds. ##STR4##

As described hereinabove, the moieties R₃, R₄, and R₅ in Formula (1) andin any of the Formulae disclosed herein that contain any of R₃, R₄, orR₅, are independently hydrogen, C₁ -C₆ alkyl protected hydroxy or C₁ -C₈alkoxy. There are preferably no electrophilic centers on the compound ofFormula (1) susceptible to attack by a phenolate anion under thepreferred reaction conditions described below.

Specifically preferred ortho-halo phenolic compounds of Formula (1) is2-chlorophenol, while an especially preferred compound of Formula (1) is2-bromo-5-methoxyphenol, which is also known as4-bromo-3-hydroxyanisole. Many suitable ortho-halo phenolic compoundsare available from commercial supply houses, e.g., Aldrich ChemicalCompany (Milwaukee, Wis.). The preparation of 2-bromo-5-methoxyphenol isdescribed in, e.g., de Paulis, T. et al., J. Med. Chem., 28, 1263-1269,1985.

Chiral electrophiles useful in the inventive methodology are representedby the Formula (2).

    R.sub.2 -L

    Base                                                       Formula (2)

In Formula (2), the designation "L" represents a leaving group. As usedherein, the term "leaving group" denotes an atom or atomic arrangementthat is sufficiently stable in anionic form to detach from a carbon atomin response to nucleophilic attack at that carbon by a phenolic oxygenatom. Exemplary leaving groups include chloride, bromide and iodide.Many hydroxyl derivatives, e.g., derivatives prepared by the conversionof a hydroxyl group into an ester of a relatively strong acid, areleaving groups according to the invention. Exemplary hydroxyl groupderived leaving groups include, without limitation, para-toluenesulfonylester (tosylate group), or methanesulfonyl ester (mesylate group) andthe like. Chloride is a preferred leaving group "L" according to theinvention.

In addition to a leaving group, the compounds of Formula (2) have an R₂moiety, where the R₂ moiety has at least one chiral center, and theleaving group "L" is bonded to the R₂ moiety.

Suitable R₂ moieties according to the invention include, but are notlimited to, the anomers, enantiomers and diastereomers of (1)carbohydrates and derivatives thereof including oligosaccharides, (2)terpenes and derivatives thereof including diterpenes andsesquiterpenes, and (3) amino acids and derivatives thereof includingpolypeptides. Preferably, the heteroatom(s) in R₂ is nitrogen, oxygenand/or sulfur, with oxygen in the form of one or more ether groups, asin carbohydrates and derivatives thereof, being most preferred.

Preferred carbohydrates and derivatives thereof that form the R₂ moietyinclude, but are not limited to, the furanose or pyranose forms of anyof D-sugars, especially D-glucose, D-mannose and D-galactose, includingoligomers thereof, also known as oligosaccharides. The carbohydratederivatives preferably have all of their free hydroxyl groups inprotected form. Preferably, the hydroxyl groups in protected form areunreactive with base or nucleophiles, such as an acetonide group(isopropylidene ketal) or benzyl or paramethoxybenzyl groups, and thelike.

Preferred compounds of Formula (2) derived from terpenes or derivativesthereof include, but are not limited to, (-)-isopinocamphyl chloromethylether, (+)-isopinocamphyl chloromethyl ether,(2R,2S,5R)-chloromethyl-(-)-menthol,(1S,2R,5S)-chloromethyl-(+)-menthol,(-)-chloromethyldicyclohexylsulfamoyl-D-isoborneol and(+)-chloromethyldicyclohexylsulfamoyl-L-isoborneol and the like. Whilethe aforelisted terpene-derived compounds of Formula (2) have a chlorideleaving group, other leaving groups as previously defined may besubstituted for the chloride according to the invention.

Preferred compounds of Formula (2) derived from amino acids orderivatives thereof include, but are not limited to, 2-chloromethyl4(S)-C₁₋₅ alkyl oxazoline wherein C₁₋₅ alkyl is preferably isopropyl,2-chloromethyl-4-(R)-C₁₋₅ alkyl oxazoline wherein C₁₋₅ alkyl ispreferably isopropyl, 2-chloromethyl-4-(S)-C₆₋₁₂ aryl oxazoline whereC₆₋₁₂ aryl is preferably phenyl but may also be C₁₋₅ alkyl-substitutedphenyl or naphthyl, 2-chloromethyl 4(R)-C₆₋₁₂ aryloxazoline where C₆₋₁₂aryl is preferably phenyl but may also be alkyl-substituted phenyl ornaphthyl, and the like. While the aforelisted preferred amino acidderived compounds of Formula (2) have a chloride leaving group, otherleaving groups as previously defined may be substituted for the chlorideaccording to the invention.

It is preferred that R₂ is a carbohydrate in the D-form. Particularly inthe case where the R₂ moiety is a carbohydrate, but in other appropriateinstances as well, the hydroxyl groups of R₂ may need to be protectedfrom undesired reactions, i.e., the hydroxyl groups may need to be a"protected hydroxyl" group as that term has been previously definedherein. A preferred compound of Formula (2) is known as2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyl chloride and has theFormula (2A) shown below. The β-anomer, i.e.,2,3:5,6-di-O-isopropylidene-β-D-mannofuranosyl chloride (not shown) isanother preferred compound of Formula (2). ##STR5## Compounds of Formula(2) are known in the chemical literature; see e.g., Ronald et al., J.Org. Chem. 1980, 45, 2224-2229. The compound of Formula (2A) can beprepared from diacetone-D-mannose according to procedures described inNicolaou, K. C., et al., Tet. Lett. 25, 2295 (1984) and references citedtherein, where the Nicolaou reference is incorporated herein byreference.

According to the invention, compounds of Formula (1) and (2) arecontacted in the presence of base, preferably in the further presence ofsolvent, to prepare a compound of Formula (3). Suitable bases includeone or more of the alkali metal hydroxides and alkoxides, includinglithium hydroxide, sodium hydroxide and potassium hydroxide, and C₁₋₅alkoxides such as sodium C₁₋₅ alkoxides including sodium ethoxide, andpotassium C₁₋₅ alkoxides including potassium t-butoxide, and the like.Other suitable bases include tertiary amines such as DBU(1,8-diazobicyclo[5,4,0]undec-7-ene); alkali metal hydrides such assodium hydride; alkali metal amides, such as lithiumbis(trimethylsilylamide) and alkali; metal organometallics, wherein theorgano moiety preferably contains 1-5 carbon atoms, such as n-butyllithium, sec-butyl lithium and t-butyl lithium. Preferred bases includelithium hydroxide, sodium hydroxide, potassium hydroxide, sodium C₁₋₅alkoxide, potassium C₁₋₅ alkoxide, DBU, sodium hydride, potassiumhydride, lithium bis(trimethylsilylamide), n-butyl lithium, t-butyllithium and sec-butyl lithium. More preferred bases include potassiumt-butoxide, sodium hydride and DBU.

The solvent useful for the preparation of the Formula (3) compoundshould be inert to reaction with strong base, and be capable ofdissolving the Formula (1) and Formula (2) compounds. Suitable solventsinclude one or more of aliphatic polyether, tetrahydrofuran (THF),toluene, diethyl ether and methyl t-butyl ether. Preferred solventsinclude 1,2-dimethoxyethane, diglyme also known as di-ethylene glycoldimethyl ether, which is a preferred aliphatic polyether, toluene, andthe like.

According to a preferred process of the invention, a compound of Formula(1) is dissolved in a solvent under an inert atmosphere and cooled toabout 0° C. to about 25° C. A base is then added with stirring, forsufficient time, for example, about 15 minutes to form the correspondingphenoxide, to which a compound of Formula (2) is added gradually. Atleast about 1 molar equivalent of base is preferably added per mole ofhalo-phenol compound of Formula (1), and preferably between about 1.0molar and about 1.5 molar equivalents of base are added per mole ofcompound of Formula (1) in order to obtain a high yield of the desiredproduct. The compounds of Formulae (1) and (2) may be contacted inequimolar or nonequimolar amounts. Whichever of the compounds ofFormulas (1) or (2) is the least expensive is preferably present inmolar excess relative to the other compound. When a compound of Formula(1) is dissolved in a solvent prior to contact with base, the compoundis suitably dissolved at a concentration of from about 0.1 to about 10molar, preferably from about 0.3 to about 3 molar.

The reaction mixture comprising solvent, base and compounds of Formulae(1) and (2) may be warmed to a temperature effective to form theresulting product. Preferably the temperature is in the range of aboutroom temperature to about the reflux temperature of the solvent orsolvent mixture employed in the reaction. Preferably, a reactiontemperature of about 50° C. to about 120° C. is employed, and morepreferably a reaction temperature of about 80° C. to about 90° C. isemployed. The reactants are preferentially heated and maintained attemperatures sufficient for an appropriate amount of time until theformation of the compound of Formula (3) is essentially complete. Areaction time of about one to about five hours is typically necessary.The product mixture comprising the compound of Formula (3) may beworked-up in a typical manner, as known to one of ordinary skill in theart. A preferred work-up method is to add water to the product mixtureand then extract the compound of Formula (3) into a water-immisciblesolvent. Traces of residual compound of Formula (1) may be removed bysimply washing the organic extract with dilute aqueous sodium hydroxidesolution.

Thus, under the most preferred reaction conditions, compounds of Formula(1) and Formula (2) are contacted in the presence of a solvent such asan aliphatic polyether, tetrahydrofuran, toluene, diethyl ether andmethyl i-butyl ether or mixtures thereof, and a base such as alkalimetal hydroxide, alkali metal C₁₋₅ alkoxide, alkali metal hydride,alkali metal amide, alkali metal organometallic or tertiary amine, at areaction temperature of from about room temperature to about the refluxtemperature of the solvent or solvent mixture. More preferably, thesolvent is 1,2-dimethoxyethane, tetrahydrofuran or toluene, the base issodium hydride, potassium t-butoxide or DBU, and the reactiontemperature is from about 50° C. to about 110° C.

The process of the invention offers the advantage that further syntheticmanipulation of the compound of Formula (3) can be accomplished withoutthe need to isolate and purify the compound of Formula (3). Thus, afterthe compound of Formula (3) has been extracted into a water-immisciblesolvent as described above, the solution of the Formula (3) compound maybe used directly in, e.g., the synthetic scheme outlined in Scheme 1.Alternatively, the compound of Formula (3) may be isolated in purifiedform by techniques known to the skilled artisan, such as, e.g.,distillation, crystallization and/or chromatography.

Alternatively, and in a similar manner, the compound of Formula (1) maybe added to a solution of a base, and then the compound of Formula (2)added to the mixture of base and Formula (1) compound. Less preferably,the compounds of Formulae (1) and (2) can be combined and then baseadded to the combination.

Preferably, a single anomeric, enantiomeric or diastereomeric form of acompound of Formula (2) is reacted with a compound of Formula (1). Thus,if R₂ has a single chiral center, then the compound of Formula (2) ispreferably a single enantiomer of the two possible enantiomers, or asingle anomer of the two possible anomers. Furthermore, if R₂ has twochiral centers, then the compound of Formula (2) is preferably a singleone of the possible diastereomeric forms of the compound of Formula (2).In the event that more than one anomeric, enantiomeric or diastereomericform of R₂ is present in a compound of Formula (2), then preferably asingle anomeric, enantiomeric or diastereomeric form is present inexcess over the other anomeric, enantiomeric or diastereomeric form(s),where the excess is preferably at least about 75% anomeric, enantiomericor diastereomeric excess, more preferably at least about 90% anomeric,enantiomeric or diastereomeric excess, and still more preferably atleast about 98% anomeric, enantiomeric or diastereomeric excess. Duringthe reaction to transfer the R₂ moiety to the compound of Formula (1),the anomeric, enantiomeric or diastereomeric integrity of R₂ isretained. For convenience, the term "diastereomeric" may be used hereinto refer to any of anomeric, enantiomeric or diastereomeric.

The process of the invention thus provides for the preparation ofcompounds of Formula (3). ##STR6## wherein R₁, R₂, R₃, R₄, and R₅ are asdefined hereinabove. It is to be noted that it is preferrred that thecompounds of Formula (3) do not have R₁ equal to bromo and R₄ equal tomethyl when R₂ is (isopinocamphyloxy)methyl. Thus, in the processdescribed above, when the compound of Formula (1) has R₁ equal to bromoand R₄ equal to methyl, then the compound of Formula (2) does not haveR₂ equal to (isopinocamphyloxy)methyl.

Highly preferred compounds of Formula (3) are those wherein each of R₃,R₄, and R₅ are independently selected from the group consisting ofhydrogen, protected hydroxyl, C₁₋₅ alkyl and C₁₋₅ alkoxy, and wherein R₂is a halide of the carbohydrate or derivative thereof, such as2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyl chloride,2,3:5,6-di-O-isopropylidene-β-D-mannofuranosyl chloride. Other R₂moieties include (-)-isopinocamphyl chloromethyl ether,(+)-isopinocamphyl chloromethyl ether,(2R,2S,5R)-chloromethyl-(-)-menthol,(1S,2R,5S)-chloromethyl-(+)-menthol,(-)-chloromethyldicyclohexylsulfamoyl-D-isoborneol,(+)-chloromethyldicyclohexylsulfamoyl-L-isoborneol,2-chloromethyl-4(S)-isopropyloxazoline,2-chloromethyl-4-(R)-isopropyloxazoline,2-chloromethyl-2(S)-phenyloxazoline or2-chloromethyl-4-(R)-phenyloxazoline.

Especially preferred compounds of Formula (3) are2-bromo-5-methoxyphenyl 2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside,2-bromo-5-methoxyphenyl 2,3:5,-di-O-isopropylidene-b-D-mannofuranoside,2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy)chlorobenzene, and5-chloro-2-(2,3:5,6di-O-isopropylidene-a-D-mannofuranosyloxy)bromobenzene.

A most preferred compound of Formula (3) is 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside, depicted in Formula(3A). The β-mannofuranoside diastereomer (not shown) of themethoxybromobenezene of Formula --(3A) is also a preferred compound ofFormula (3) according to the invention. ##STR7##

Another aspect of the invention is the conversion of a compound ofFormula (3) into a reactive organometallic intermediate, followed byreaction of the intermediate with a cyclopentenone of Formula (4) toform a composition comprising diastereomerically-related compounds (5A)and (5B) having Formulae (5A) and (5B), respectively, as set forth inScheme 1.

The compound of Formula (4) has the structure shown below: ##STR8##

In Formula (4), A, B, G, D, Z and Z₁₁ are as defined hereinabove. R₁₀,as defined herein, is C₁₋₅ alkyl; however the exact identity of R₁₀during the formation of the composition of compounds (5A) and (5B) isnot particularly critical because it can be readily changed at any timeby transesterification or functional group manipulation using techniquesknown to one of ordinary skill in the art. R₁₀ is most preferablymethyl.

Compounds of Formula (4) are known in the chemical literature, andvariations thereof may be prepared by simple variations on the chemistryalready set forth in the literature, using knowledge available to one ofordinary skill in the art. PCT publication number WO/9308799-A1,published May 13, 1993, discloses exemplary and preferred chemistry forthe preparation of compounds of Formula (4). The entire disclosure ofWO/9308799 is incorporated herein by reference. A preferred compound ofthis disclosure is methyl3-(3,4-methylenedioxyphenyl)-6(prop-1-yloxy)-1-oxo-indene-2-carboxylate.

Compounds (5A) and (5B) may be prepared via a process that begins withthe conversion of a compound of Formula (3) into a reactiveorganometallic intermediate. Formation of the reactive organometallicintermediate is achieved through conversion of the carbon atom to whichthe R₁ halogen atom is attached, into a nucleophilic center, i.e., theorganometallic intermediate is prepared by halogen metal exchange from acompound of Formula (3). Methods to accomplish halogen metal exchangewith an aryl halide to form an aryl reactive organometallic intermediateare known in the art, and include, e.g., reaction of an aryl halide withan alkyl lithium reagent such as butyl lithium.

The initially formed reactive organometallic intermediate may besubjected to one or more transmetallation reactions. For example, afterhalogen metal exchange of a compound of Formula (3) with an alkyllithium reagent, the so-formed reactive organometallic intermediate maybe treated with a second metal-containing reagent, such as a magnesiumcompound, e.g., magnesium bromide, to effect transmetallation and thusform an organomagnesium intermediate from the initially formedorganolithium intermediate. As used herein, a reactive organometallicintermediate is the result of halogen metal exchange, optionallyfollowed by one or more transmetallation reactions or a result of directtreatment of compound of Formula (3) with a metal.

According to a preferred process for forming a composition comprisingcompounds (5A) and (5B), a solution is formed by dissolving a compoundof Formula (3) in a suitable solvent, where exemplary suitable solventsare inert and include THF, toluene, heptane, and the like. A suitableconcentration of the compound of Formula (3) in the solvent is in therange of about 0.2 to about 0.7 molar, and is more preferably about 0.3molar. To the solution may also be added one or more additives such asof N,N,N',N'-tetramethylethylenediamine (TMEDA) andN,N'-dimethylpropyleneurea (DMPU), and the like which are usefulchelating agents for halogen metal exchange reactions with alkyllithiums, as recognized in the art. The solution of Formula (3) compoundis cooled to less than about 0° C., preferably less than about -70° C.The cooled solution of Formula (3) compound is treated with about oneequivalent of an alkyl lithium reagent, such as n-BuLi. The alkyllithium reagent is preferably predissolved in a suitable solvent orcombination of solvents, for example, one or more of tetrahydrofuran,toluene and heptane, and the like. Other alkyl lithium reagents, such assec-butyl lithium and t-butyl lithium, may alternatively be employed inthe process.

After halogen metal exchange is complete or substantially complete, drymagnesium halide, e.g., MgBr₂.Et₂ O, added to effect transmetallation,and the reaction mixture allowed to warm to about room temperature forsufficient time, e.g., a couple hours, to ensure complete formation ofan organomagnesium intermediate commonly referred to as a Grignardspecies. A slight molar excess of the dry magnesium halide, e.g.,MgBr₂.Et₂ O, compared to the moles of compound of Formula (3) utilizedin the process, is employed to ensure complete conversion of theorganolithium intermediate to the organomagnesium intermediate (Grignardspecies). Alternatively, a compound of Formula (3) may be treated withmagnesium metal (turnings or powder) at sufficient temperatures, such asbetween about 0° C., and 50° C., in a suitable solvent, as describedabove, to form the same Grignard species directly.

After ensuring formation of the organomagnesium intermediate (Grignardspecies), and cooling the Grignard species down to less than about -70°C., a THF solution of a cyclopentenone of Formula (4) is slowly added tothe solution, while maintaining the low temperature. The cyclopentenonemay be predissolved in a suitable solvent such as THF. After a couplehours, the reaction mixture is quenched with a proton source, and thenallowed to come to room temperature. Workup is conveniently accomplishedby, for example, washing the organic solution with aqueous brine ordeionized water.

The invention thus provides for a composition comprising compounds (5A)and (5B) having Formulas (5A) and (5B) respectively, in a (5A):(5B)molar present ratio of from 100:0 to 0:100. The compounds (5A) and (5B)have the structures shown below, and are in a diastereomericrelationship to one another, according to terminology commonly used byone of ordinary skill in the art: ##STR9##

In the Formulae (5A) and (5B), the moieties R₂, R₃, R₄, R₅, A, B, G, D,Z, R₁₀ and R₁ 1 are as defined hereinabove. Preferred moieties incompounds of Formulae (3) and (4) are also preferred moieties incompounds of Formulas (5A) and (5B).

As indicated hereinabove, R₂ is selected from the group consisting ofanomers, enantiomers and diastereomers of (1) carbohydrates andderivatives thereof (2) terpenes and derivatives thereof and (3) aminoacids and derivatives, thereof. The use of these R₂ groups is one of thekeys to the present inventions and is one of the reasons why the presentsynthesis accomplishes the objectives described hereinabove. As shownhereinabove and described in more detail hereinbelow, the compound ofFormula 3 containing R₂ is converted to a Grignard reagent. The R₂ groupnot only imparts chirality to the Grignard, but when it reacts with theketone of Formula 4, the resulting product is not only stable, but thepresence of the R₂ groups promotes the crystallization of 5A (or 5B)described hereinbelow so as to permit easy separation of thediastereomers, thereby avoiding the necessity of utlizing chromatographyfor separating the diastereomers. This technique which was not realizedheretofore, has been successfully exploited in the present invention, asdescribed hereinbelow.

Moreover, due to the influence of the chiral moiety R₂, the addition ofthe reactive organometallic intermediate derived from the compound ofFormula (3), to the cyclopentenone of Formula (4), proceeds with highdiastereoselectivity. That is, depending on the identity of R₂, acompound of either Formula (5A) or (5B) will be formed as the majorcomponent of a diastereomeric mixture of compounds having theseFormulae. Thus, preferably, the (5A):(5B) molar percent ratio excludes50:50, so that one of the diastereomerically-related compounds (5A) and(5B) is present in excess, and the compound in excess is denoted as thepredominant isomer and the compound not in excess is denoted as theminor isomer. More preferably, the molar percent ratio of thepredominant isomer to the minor isomer is 100:0 to about 75:25, stillmore preferably the molar percent ratio of the predominant isomer to theminor isomer is 100:0 to about 85:15, yet still more preferably themolar percent ratio is from 100:0 to about 95:5, and most preferably themolar percent ratio is from 200:0 to about 99:1. It is preferred that 5Ais the predominant isomer.

As used herein, the term "molar percent ratio", such as used for examplein the term "(5A):(5B) molar percent ratio of from 200:0 to 0:100", andwhen referring to any other pair of compounds in this specification,means that the total moles of the first listed compound, in this case(5A), divided by the total moles of both listed compounds, in this case(5A)+(5B), multiplied by 100, appears before the colon of the molarpercent ratio, while the total moles of the second listed compound, inthis case (5B), divided by the total moles of both listed compounds, inthis case (5A)+(5B), multiplied by 100, appears after the colon. Thus,the sum of the numbers on either side of the colon in a molar percentratio as used herein will always equal 100. When a range is stated, asin 100:0 to 0:100, this means that the stated composition includescompositions having 100% of the first listed compound and none of thesecond listed compound, none of the first listed compound and 100% ofthe second listed compound, and all ratios in between such as 60:40,50:50 and 40:60, to name a few. The expressions "100:0 to 0:100" and"(100-0):(0-100)" are synonymous.

A most preferred composition of compounds (5A) and (5B) is a mixture of(R) and(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate.

Another most preferred composition of compounds (5A) and 5(B) is amixture of (R) and(S)-5-Methyl-5-(1,3-benzodioxol-5-yl)-7-[2-(2,3:5,6-di-O-isopropylidene)-.alpha.-D-mannofuranosyloxy-4-methoxyphenyl]-7-hydroxy-7H-1-pyrindine-6-carboxylate.

According to another aspect of the invention, a composition comprisingcompounds of Formulas (5A) and (5B) may be subjected to one or morepurification protocols in order to obtain either of the compounds (5A)or (5B) in essentially pure form. The composition of compounds ofFormulas (5A) and (5B) is preferably obtained according to thepreviously described process starting with compounds of Formulas (3) and(4) so that one of the compounds (5A) or (5B) is the predominant isomer.The predominant isomer is preferably purified and isolated bycrystallization.

According to a preferred crystallization process of the invention, thecomposition of compounds (5A) and (5B) is combined with one or moresolvents to provide a homogeneous solution or emulsion at a firsttemperature. The solvent may be a pure or substantially pure solvent,such as n-butanol or isopropanol, or a mixture of solvents whereexemplary solvents include ethyl acetate, hexane, n-butanol, isopropanoland water. Preferred mixtures are water with n-butanol or isopropanol,and ethyl acetate with hexane. More preferred mixtures are n-Butanolwith up to 20% water and isopropanol with up to 20% water. It is mostpreferred that the solvent is n-Butanol. The combination of solvent andcomposition comprising compounds of Formulae (5A) and (5B) is thencooled to a second temperature, and if a seed of the predominant isomeris available, such a seed is added to the combination. During such acrystallization process, the mixture is preferably stirred, and thepredominant isomer will gradually crystallize out of solution. Astirring time of about 20-48 hours is typical. After filtration of thecrystal/mother liquor combination, crystals are isolated which containgreater than about 90% by weight of the predominant isomer, preferablygreater than about 95%, and more preferably greater than about 98% byweight of the predominant isomer.

The first temperature is at least high enough to achieve completedissolution of the compounds of Formulae (5A) and (5B) in the selectedsolvent or solvent pair used for the crystallization. A suitable firsttemperature is about 50-60° C. The second temperature is necessarilylower than the first temperature, and may be as low as room temperatureor even 0° C. or lower with the preferred temperature being in the range0 to 25° C.

The composition of compounds of Formulae (5A) and (5B) that may besubjected to the above crystallization process are all of thecompositions encompassed within the description of the compounds (5A)and (5B) set forth previously. Preferred compositions of compounds ofFormulae (5A) and (5B) for the crystallization process are the preferredcompositions of compounds of Formulae (5A) and (5B) set forthpreviously.

The compound(R)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylatecan be isolated in essentially pure form (greater than 98%diastereomeric excess) from mixtures ranging from 65:35 or greater of(R)-:(S)-methyl-3-(3,4-methylenedioxyphenyl-1-hydroxy-1-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate,using the crystallization process according to the invention.

The minor isomer may also be isolated by techniques known to the skilledartisan. The minor isomer is isolated from the mixture after theisolation of the major isomer. A preferred protocol for isolation of theminor isomer uses silica gel column chromatography. A preferred solventfor use in the chromatographic method is a combination of ethyl acetateand hexanes.

Another aspect of the invention is the stereoselective hydrogenation ofa composition comprising compounds (5A) and (5B), which are preferably adiastereomeric pair, in a (5A):(5B) molar percent ratio of from 100:0 to0:100, to afford a composition comprising compounds (6A) and (6B), whichare preferably a diastereomeric pair, in a (6A):(6B) molar percent ratioof from 100:0 to 0:100.

The compounds (6A) and (6B) have the Formulae (6A) and (6B)respectively, as shown below. ##STR10##

In the compounds of Formulae (6A) and (6B), R₂, R₃, R₄, R₅, A, B, D, G,Z, R₁₀ and R₁₁ are as defined hereinabove.

A preferred composition comprising compounds (6A) and (6B), which may beformed by the hydrogenation chemistry of Scheme 2, is where the compound(6A) is methyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylateand the compound (6B) is methyl-(1R, 2R,3R)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6di-O-isopropylidene-α-D-mannofuranosyloxy)4-methoxyphenyl]-5-propoxyindane-2-carboxylate.In this preferred composition, the (6A):(6B) molar percent ratio ispreferably about (100-95):(0-5), or is about (0-5):(100-95). --Thehydrogenation reaction of the invention, as shown in Scheme 2,stereoselectively hydrogenates a composition comprisingdiastereomerically-related compounds of Formulae (5A) and (5B). Pure orsubstantially pure hydrogen gas is preferably used in the hydrogenationreaction. In another embodiment a mixture of hydrogen gas and one ormore inert gases is employed. Nitrogen and argon are suitable inertgases that can be mixed with hydrogen gas, where an equal molar mixtureof hydrogen and nitrogen gases may be employed.

The hydrogen gas or mixture thereof is preferably contacted withcompounds of Formulae (5A) and (5B) under a pressure and temperaturesufficient to transform 5A to 6A or 5B to 6B. Preferably the pressureutilized is greater than atmospheric pressure, where a suitable pressureis within the range of about 10 psi to about 400 psi, preferably about50 psi to about 200 psi, and more preferably about 80 psi to about 110psi. The temperature at which the hydrogen gas and compounds of Formulas(5A) and (5B) are contacted may vary over a wide range, but the reactionis conducted at a temperature (and pressure) effective in producing thecompounds of Formula 6A from 5A (or 6B from 5B). A preferred temperatureis within the range of about 10° C. to about 60° C., where a morepreferred range is about 15° C. to about 50° C. and a most preferredrange is about 20° C. to about 30° C.

The compounds of Formulae (5A) and (5B) are preferably dissolved in aninert solvent prior to being contacted with hydrogen gas, whereexemplary suitable solvents include C₁ -C₅ alcohols and C₁ -C₅ alkylacetates, and the like. Preferred exemplary solvents are ethyl acetate,methanol and ethanol and the like. Ethyl acetate is particularlypreferred. A suitable concentration of compounds of Formulae (5A) and(5B) in the solvent is about 0.01 molar to about 0.3 molar, preferablyabout 0.1 molar to about 0.2 molar, and more preferably about 0.1 molarto about 0.15 molar which corresponds to about 100 g of compounds ofFormulae (5A) and (5B) in one (1) liter of solvent.

The hydrogenation reaction is preferably conducted in the presence of ahydrogenation catalyst, where suitable hydrogenation catalysts arecommercially available and well known in the art. Exemplaryhydrogenation catalysts include, without limitation, platinum oxide,palladium on alumina, palladium hydroxide on carbon and palladium oncarbon. Preferably, the catalyst is palladium on alumina, palladiumhydroxide on carbon or palladium on carbon, where palladium on carbon isa more preferred catalyst. The amount of metal, e.g., palladium orplatinum, on a support, e.g., carbon or alumina, can vary over a widerange. For example, catalysts having from about 1% to about 20%palladium on carbon are known and may be used in the invention. Apreferred palladium on carbon (Pd/C) catalyst has about 5% to about 15%palladium on carbon, and more preferably has about 10% to about 15%palladium on carbon. There are several different types of carbon thatmay be used as the support, e.g., charcoal, and the like.

Palladium on carbon catalysts are well known in the art, and may beobtained from many commercial supply houses, e.g., Aldrich ChemicalCompany (Milwaukee, Wis.) or Precious Metal Corp. (Sevierville, Tenn.)as their product Type # 1910 having 15% palladium on carbon, where thenumber 1910 indicates a specific type of carbon.

Hydrogenation catalysts may be basic, neutral or acidic. Typically,supply houses do not specify the acidity of the catalyst, as thisparameter is not often of importance in hydrogenation reactions. Indeed,the same supplier may provide two batches of catalyst where one batchmay be acidic and the other batch may be basic. However, in order toachieve high stereoselectivity in the hydrogenation of a compositioncomprising compounds of Formulae (5A) and (5B), it has been discoveredthat the pH of the catalyst is a very important processing factor. Thus,if an acidic catalyst is employed in the hydrogenation reaction, thestereoselectivity of the reaction is reduced compared to a reaction runin the presence of a slightly basic or neutral catalyst. Therefore, thehydrogenation catalyst preferably has a pH of greater than about 6, morepreferably has a pH between about 6.5 and about 8, and still morepreferably has a pH of about 6.8 to about 7.5. It is thus preferred thatthe Pd/C hydrogenation catalyst be neutral or slightly basic. PreciousMetal Corp. will provide their Type # 1910 15% palladium on carbon asessentially a neutral catalyst, 50% water wet, and this catalyst ispreferred for the hydrogenation reaction of the invention. Commerciallyavailable acidic catalysts may be used if washed sufficiently with waterat about neutral pH to thereby provide a neutral catalyst.

The hydrogenation reaction of Scheme 2 is preferably conducted withagitation. That is, a stirrer is preferably present in the reactionvessel, to provide for stirring of the mixture of catalyst, solvent andcompounds of Formulae (5A) and/or (5B). In this way, the surface of thecatalyst comes into periodic contact with the hydrogen atmosphere. Theprogress of the reaction may be determined by periodically pullingsamples and analyzing those samples by an appropriate analytical method,e.g., by HPLC. The uptake of hydrogen may also be monitored, andcompared to the theoretical uptake, in order to gauge the progress ofthe hydrogenation reaction. In general, when the hydrogenation reactionis conducted at about ambient temperature, i.e., about 25° C., areaction time of between about 2 to about 48 hours is usually required.

Preferably, the hydrogenation reaction proceeds with highstereoselectivity. That is, a compound of Formula (5A) is hydrogenatedto form almost exclusively a compound of Formula (6A), while a compoundof Formula (5B) is hydrogenated to form almost exclusively a compound ofFormula (6B). The term "almost exclusively" means that at least about90%, preferably at least about 95% and more preferably at least about98% of the compound of Formula (5A) or (5B) will be converted to acompound of Formula (6A) or (6B), respectively. Thus, if the (5A):(5B)molar percent ratio of compounds of Formulas (5A) and (5B) in thestarting material is about (100-90):(0-10) (compound of Formula (5A) inexcess) or about (0-10):(100-90) (compound of Formula (5B) in excess),then the (6A):(6B) molar percent ratio of the compounds of Formulas (6A)and (6B) in the product will also be about (100-90):(0-10) (compound ofFormula (6A) in excess when the starting composition had the compound ofFormula (5A) in excess) or about (0-10):(100-90) (compound of Formula(6B) in excess when the starting composition had the compound of Formula(5B) in excess).

The chemistry in Scheme 2 thus illustrates the process wherein acomposition comprising compounds (5A) and (5B) in a (5A):(5B) molarpercent ratio of from 100:0 to 0:100 is selected and then contacted withhydrogen gas in the presence of a basic or neutral hydrogenationcatalyst to achieve a hydrogenation reaction. Preferably, thehydrogenation catalyst is about 10 wt. % to about 15 wt. % palladium oncarbon having a pH of about 6.8 to about 7.5, and the hydrogenationreaction is conducted in the presence of ethyl acetate as a solvent. Themolar percent ratio of compounds (5A):(5B) in the starting material issubstantially the same as the molar percent ratio of compounds (6A):(6B)formed as products. A preferred composition comprising compounds (5A)and (5B) is at least one of (R)- and(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate.

After the hydrogenation reaction is complete, the product mixture isoptionally filtered to separate the hydrogenation catalyst from thesolvent and dissolved materials. It is convenient to filter the reactionmixture through Celite to obtain a solubilized product mixture ofcompounds of Formulae (6A) and (6B). Other filter aids known in the artmay also be employed.

The composition comprising compounds (6A) and (6B) is optionallysubjected to further purification in order to obtain one of thecompounds (6A) or (6B) in essentially pure form. A preferredpurification procedure is crystallization. Using crystallization,crystals formed essentially of only a single one of the compounds (6A)or (6B) may be obtained. The isomeric purity of the crystals willdepend, in part, on the identity of the solvent from which the crystalsform. Absolute ethanol is a preferred solvent, because it provides forthe formation of crystals having a single isomer in very highenantiomeric or diastereomeric purity. However, other solvents may alsobe used in the crystallization process, and will provide for crystals ofenhanced isomeric purity, where the degree of purity depends in part onthe specific structures of the compounds (6A) and (6B). Suitablesolvents for the crystallization include, without limitation, ethanol,optionally containing about 1% to about 5% of a second solvent such astoluene, methanol or ethyl acetate, and absolute ethanol, optionallycontaining up to about 10% of a second solvent such as toluene, methanolor ethyl acetate. Absolute ethanol with up to about 10% ethyl acetate isa preferred crystallization solvent, while absolute ethanol without anyco-solvent is more preferred.

In general, the crystallization process dissolves compounds (6A) and(6B) in a solvent at an elevated dissolution temperature, and then holdsthe mixture at a crystallization temperature lower than the dissolutiontemperature while crystals form. The precise dissolution andcrystallization temperatures can vary over wide ranges, and will dependon the solubility and concentration of the compounds (6A) and (6B) inthe crystallization solvent. One of ordinary skill in the art candetermine these temperatures and suitable concentrations without undueexperimentation. A suitable crystallization temperature is less thanabout 40° C., is preferably about 20° C. to about 40° C., and is morepreferably about 30° C. to about 40° C.

According to a preferred purification process, the composition ofcompounds (6A) and (6B) is heated to reflux in order to distill off someof the solvent used in the hydrogenation reaction. Then thecrystallization solvent, e.g., ethanol, is added and the resultingmixture again heated to reflux to distill off more of the hydrogenationsolvent. Several chases may be necessary to replace essentially all ofthe hydrogenation solvent with ethanol. After a solution of thecomposition of compounds (6A) and (6B) in ethanol has been formed at anelevated dissolution temperature, the solution is cooled with gentlestirring. Preferably, the solution is cooled to a crystallizationtemperature of about 200C to about 40° C. In this temperature range, andafter a few hours of stirring, crystals enriched in one of the compounds(6A) or (6B) will form and can be isolated by, techniques known to theskilled artisan e.g., filtration.

Preferably, after the crystallization process, a single one of thediastereomerically-related compounds (6A) and (6B) may be obtained ascrystals having very high diastereomeric excess, e.g., a diastereomericexcess greater than about 75%, preferably greater than about 90%, morepreferably greater than about 95% and still more preferably greater thanabout 98% diastereomeric excess.

The invention further provides for a compound of Formula (6A) to beconverted to a compound of Formula (7A) according to the chemistryoutlined in Scheme 3, Routes (A) and (B). While the chemistry outlinedin Scheme 3 is illustrated starting with a compound of Formula (6A) forconvenience, it should be understood that the same chemistry can be usedto convert a compound of Formula (6B) to a compound of Formula (7B), andto convert a composition comprising compounds of Formulae (6A) and (6B),having a (6A):(6B) molar percent ratio of 100:0 to 0:100, to acomposition comprising compounds of Formula (7A) and (7B), having a(7A):(7B) molar percent ratio of 100:0 to 0:100. As explainedpreviously, compounds of Formulas (7A) and (7B) are useful as endothelinreceptor antagonists.

Looking first at Scheme 3, Route (A), Step (1), a compound of Formula(6A) is treated with Bronsted acid. This affects cleavage of the arylether --OR₂ group in a compound of Formula (6A) and forms a phenolic--OH group in a compound of Formula (8A). The preferred acid ishydrochloric acid, which is dissolved in water at a concentration ofabout 5 wt. % to about 37 wt. %. Preferably, concentrated (con.)hydrochloric acid, i.e., 37 wt. % aqueous HCl, is the acid for thecleavage reaction. Other suitable Bronsted acids that may be employedinclude, without limitation, hydrobromic acid, phosphoric acid,hypophosphorous acid, sulfuric acid, para-toluenesulfonic acid,methanesulfonic acid and the like.

The ratio of acid to compounds of Formulae (6A) and (6B) can vary over awide range, and will depend upon the concentration of acid beingemployed. When the acid is hydrochloric acid at 37 wt. % in water, aconcentration of about 40 mL to about 200 mL acid for about 0.1 mol toabout 1 mol of compounds of Formulas (6A) and (6B) is suitable for thecleavage reaction. Preferably, about 50 mL to about 100 mL hydrochloricacid is used for about 0.1 mol to about 1.0 mol of the compounds ofFormula (6A) and (6B), where a more preferred ratio is about 70 mL toabout 80 mL acid for about 0.4 to about 0.6 mol of compounds of Formulas(6A) and (6B).

The compounds of Formulae (6A) and-(6B) are preferably slurried in asolvent prior to treatment with acid. Aliphatic alcohols or polyols, andaliphatic ethers and polyethers are suitable solvents. A preferredsolvent is a C₁ -C₄ alcohol, where methanol is a particularly preferredsolvent. An elevated temperature is preferably employed in Step (1) inorder to obtain a commercially desirable rate for the reaction. Areaction temperature of between about 20° C. to about the refluxtemperature of the reaction mixture, although preferably not greaterthan about 70° C., is suitable. Preferably, a temperature of about 50°C. to about the reflux temperature is employed, while a more preferredtemperature is at the reflux temperature of the reaction mixture. Thereaction will be slower at lower temperatures. Preferably, methanol isused as the solvent in Step (1) and the reaction temperature is aboutthe reflux temperature of the reaction mixture including methanol, i.e.,about 60° C. to about 65° C. The progress of the reaction may bemonitored by periodically pulling samples and analyzing the samples byan analytical technique, e.g., by HPLC.

An optional but preferred Step (1) includes a purification step afterthe formation of a compound of Formula (8A). A preferred purificationstep begins with the compound of Formula (8A) at about the refluxtemperature of the reaction mixture that includes the compound ofFormula (8A), where the compound of Formula (8A) is still in thepresence of the Bronsted acid. The reaction mixture is cooled to about20° C. to about 40° C., preferably about 30° C., and then a seed crystalof the desired product may be added. After continuous stirring for about18 hours at about ambient temperature, the seeded slurry may be cooledto about 0° C. to about 10° C., preferably to about 0° C. to about 5°C., for an additional 2-10 hours, preferably about 4 hours, and then theresulting crystals isolated by filtration. According to thispurification procedure of Step (1), crystals having at least about 90%by weight of a single enantiomer, preferably at least about 95% and morepreferably at least about 99% of a single enantiomer, are formed. Thecrystals may have an enantiomeric excess of greater than about 99%.

As explained above, the chemistry used to convert a compound of Formula(6A) to a compound of Formula (8A) according to Step (1) may begenerally used to prepare a composition comprising compounds (8A) and(8B), having an (8A):(8B) molar percent ratio of from 100:0 to 0:100,from a composition comprising compounds (6A) and (6B), having a(6A):(6B) molar percent ratio of from 100:0 to 0:100, wherein thecompounds (8A) and (8B) have the Formulae (8A) and (8B), respectively.##STR11##

Following Step (1) in Route (A) of Scheme 3 is Step (2), wherein aphenolic compound of Formula (8A) is alkylated to form a compound ofFormula (9A). The purpose behind the sequence of Steps (1) and (2),which have the overall effect of converting --OR₂ to --OR₁₂, is that R₂is particularly suited to allowing the formation of a compositioncomprising diastereomerically-related compounds (5A) and (5B) fromcompounds (3) and (4) where the composition is highly enriched in one ofthe two diastereomers due to the influence of R₂, while R₁₂ isparticularly suited to enhancing the efficacy of a compound of Formula(7A) as an endothelin receptor antagonist.

Alkylation chemistry for phenolic compounds is well known in the art,and any such chemistry may be used for the alkylation of a compound ofFormula (8A). Upon alkylation, a compound of Formula (9A) is prepared,where the group R₁₂ has been added to the compound of Formula (8A) toform an aryl ether.

The alkylation of Step (2) in Route (A) proceeds by contacting acompound of Formula (8A) with an alkylating agent. A preferredalkylating agent is L₁ -(CH₂)_(p) CO₂ R₁₃, where R₁₃ is a C₁₋₅ alkylgroup and p is an integer from 1 to 3. In this case, R₁₂ will be--(CH₂)_(p) CO₂ R₁₃. "L₁ " in the alkylating agent is a leaving group,where the term "leaving group" as used herein denotes an atom or atomicarrangement that is sufficiently stable in anionic form to detach from acarbon atom in response to nucleophilic attack at that carbon by aphenolic oxygen atom. Exemplary leaving groups include chloride, bromideand iodide. Many hydroxyl derivatives, e.g., derivatives prepared by theconversion of a hydroxyl group into an ester of a relatively strongacid, are leaving groups according to the invention. Exemplary hydroxylgroup derived leaving groups include, without limitation,para-toluenesulfonyl ester (tosylate group), methanesulfonyl ester(mesylate group) and alkyl esters, such as acetate ester, and the like.Chloride and bromide are preferred leaving groups "L₁ " according to theinvention, and methyl bromoacetate, i.e., L₁ =Br, p=1 and R₁₃ =CH₃, is apreferred alkylating agent for a compound of Formula (8A).

Another preferred alkylating agent is ethylene carbonate. When acompound of Formula (8A) is contacted with ethylene carbonate,preferably in the presence of base, the R₁₂ group in the compound ofFormula (9A) is --(CH₂)₂ OH.

The alkylation reaction is preferably conducted in the presence of base.Suitable bases include, without limitation, sodium hydride, potassiumhydride, potassium carbonate and the like. The potassium carbonate maybe in, e.g., powder or granular form. Other bases could also beemployed, where suitable bases are known to one of ordinary skill in theart. When the alkylating agent is ethylene carbonate, the base ispreferably potassium carbonate, and is more preferably anhydrouspowdered potassium carbonate. About 2 to about 20 equivalents of baseare suitably used per equivalent of compound of Formula (8A).Preferably, about 2 to about 8 equivalents are employed, while morepreferably about 4 to about 6 equivalents of base are employed.

The alkylation reaction is also preferably conducted in a solvent, wheresuitable solvents include, without limitation, aromatic solvents andhalogenated versions thereof such as benzene, toluene, xylenes,chlorobenzene and polychlorobenzene; and ethers such as C₃ -C₅ alkylethers. Toluene, xylenes, chlorobenzene and polychlorinated benzenes arepreferred solvents, while toluene is a particularly preferred solvent.

The reaction mixture in the alkylation reaction of Step (2) is conductedat temperatures effective to produce the desired product. Preferably,the reaction mixture in the alkylation reaction of step (2) is taken toelevated temperature, such as about 50° C. to about the refluxtemperature of the reaction mixture, in order to achieve a satisfactoryreaction rate. Preferably, the reaction temperature is about 100° C. toabout 120° C., and when toluene is the reaction solvent, the preferredtemperature is about 110° C. to about 115° C, which is the refluxtemperature of the reaction mixture.

When ethylene carbonate is the alkylating agent, it is preferred that ahigh temperature of about 100° C. to about 120° C. is preferablyemployed in order to obtain a reasonable rate for the alkylationreaction. However, at these high temperatures, lactonization between thephenolic hydroxyl group and the carboxylate ester at position 2 of theindane ring, may be a significant problem due to the particularstereochemistry of the compounds of Formulae (8A) and (8B). However, ithas been surprisingly discovered that extended reaction times atelevated temperatures may convert any lactone intermediate that doesform into the desired alkylated product.

As explained above, the chemistry used to convert a compound of Formula(8A) to a compound of Formula (9A) according to Step 2 may be generallyused to prepare a composition comprising compounds (9A) and (9B), havinga (9A):(9B) molar percent ratio of from 100:0 to 0:100, from acomposition comprising compounds (8A) and (8B), having an (8A):(8B)molar percent ratio of from 100:0 to 0:100, where the compounds (9A) and(9B) have the Formulae (9A) and (9B), respectively. ##STR12##

Thus, the chemistry described above affords a composition comprisingcompounds (9A) and (9B) having the Formulae (9A) and (9B) respectively,in a (9A):(9B) molar percent ratio of 100:0 to 0:100, wherein R₃, R₄,R₅, A, B. G. D, Z. R₁₀, R₁₁ and R₁₂ are as defined hereinabove.

A preferred composition of the compounds (9A) and (9B) are methyl (1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2-hydroxyeth-2-yloxy)4-methoxyphenyl]-5propoxyindane-2-carboxylateand methyl-(1R, 2R,3R)-2-(3,4-methylenedioxyphenyl)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl)-5-propoxyindane-2-carboxylate,respectively, and the molar percent ratio of (9A):9(B) is about(100-95):(0-5). Such a composition may be prepared by selecting acomposition comprising compounds (8A) and (8 B), wherein the compounds(8A) and (8B) are methyl-(1S, 2S, 35)-1-(3,4-and methyl-(2R, 2R,3R)-1-(3,methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate,respectively, and the molar percent ratio of (8A):(8B) is about(100-95):(0-5), and then treating the composition comprising compounds(8A) and (8B) with ethylene carbonate in the presence of potassiumcarbonate in toluene at a temperature of about 100° C. to about 120° C.

In an embodiment of the present invention, the compound of Formula (9A)is treated with base such as hydroxides, alkoxides, and the like, in thepresence of water in a suitable solvent mixture such a methanol andtetrahydrofuran to achieve saponification and epimerization of thecarboxylate group at position 2 of the compound, to thereby form acompound of Formula (7A) as shown in Route (A), Step (3) of Scheme 3.Compounds of Formula (7A) are known endothelin receptor antagonists, asreported in WO29308799 incorporated herein by reference. Specificreaction conditions saponification and epimerization reaction aregenerally known in the art. In additions examples of such reactionconditions are set forth in WO/9308799, incorporated herein byreference, and will not be further described herein.

Thus, according to Route (A) of Scheme 3, a composition comprisingcompounds (6A) and (6A), having a (6A)l(6B) molar percent ratio of from100:0 to 0:100 may be converted to a composition comprising compounds(7A) and (7B), having a (7A):(7B) molar percent ratio of from 100:0 to0:100. ##STR13##

In the formula R₃ ', R₄ ', R₅ ', A, B, D, G, Z', R₁₁ ' and R₁₂ ' are asdefine d hereinabove.

Preferably, in the chemistry outlined above, the starting materialcompositions are significantly enriched in one of thediastereomerically-related compounds of Formulas (6A&B), (8A&B) or(9A&B). The term "significantly enriched" means that the startingmaterial compositions are not racemic, i.e., they do not contain equalmolar amounts of the compounds (6A) and (6B), or equal molar amounts ofthe compounds (8A) and (8B), or equal molar amounts of the compounds(9A) and (9B). Preferably, the molar percent ratio of any two of theabove-listed diastereomerically-related compounds is about(100-75):(0-25), more preferably is about (200-90):(3-20), still morepreferably is about (100-95):(0-5), and yet still more preferably isabout (100-98):(3-2), where either of the diastereomerically-relatedcompounds (6A)/(6B), (8A)/(8B) or (9A)/(9B) may be in excess of theother.

According to another aspect of the invention, the conversion of acompound of Formula (6A) to a compound of Formula (7A) may proceedthrough Route (B) as identified in Scheme 3, where the intermediatesformed in the conversion according to Route (B) are more completelyshown in Scheme 4.

As illustrated by Step (4A) in Scheme 4, a compound of Formula (6A) maybe converted to a compound of Formula (10A) by epimerization of thecarboxylate ester at position 2. The epimerization reaction ispreferably accomplished by treating a compound of Formula (6A) with basein the presence of solvent at an elevated temperature. Suitable basesfor the reaction of Step (4A) include alkali metal hydroxides, such aslithium hydroxide, sodium hydroxide and potassium hydroxide, as well asalkali metal alkoxides, such as sodium ethoxide and sodium methoxide.Alkali metal hydroxides are preferred, with lithium hydroxide being aparticularly preferred base for the epimerization reaction.

Suitable solvents for the reaction of Step (4A) include water, loweralkyl (e.g., C₁ -C₅) ethers and lower alkyl alcohols and polyols, aswell as mixtures thereof. Water, tetrahydrofuran, methanol, ethanol andpropanol are exemplary solvents, with methanol and tetrahydrofuran incombination with water being a preferred solvent. A suitable reactiontemperature is about 20° C. to about the reflux temperature of thereaction mixture, preferably about 50° C. to the reflux temperature ofthe reaction mixture, and more preferably about the reflux temperatureof the reaction mixture.

As explained above, the chemistry used to convert a compound of Formula(6A) to a compound of Formula (10A) according to Step (4A) may begenerally used to prepare a composition comprising compounds (10A) and(10B), having a (10A):(10B) molar percent ratio of from 100:0 to 0:100,from a composition comprising compounds (6A) and (6B), having a(6A):(6B) molar percent ratio of from 100:0 to 0:100, wherein thecompounds (10A) and (10B) have the Formulae (10A) and (10B),respectively. ##STR14## In formulae 10A and 10B, R₃, R₄, R₅, R₂, A, B,D, G, Z, R₁₁ and R₁₀ are as defined hereinabove.

The basic conditions that cause the epimerization reaction forconverting a compound of Formula (6A) to a compound of Formula (10A)according to Step (4A), may subsequently cause hydrolysis of the estercompound of Formula (10A) to form the carboxylate compound of Formula(11A) according to Step (4B). However, in order for the hydrolysisreaction to proceed immediately after the epimerization reaction, somewater must be present in the reaction mixture. Thus, in an aqueoussolvent, preferably containing some lower alcohol, the basic conditionsused in Step (4A) may cause not only the epimerization of thecarboxylate ester at position 2, but also the hydrolysis of thecarboxylate ester at position 2 to form a carboxylic acid as shown inFormula (11A). If water is not present in the solvent used to convert acompound of Formula (6A) to a compound of Formula (10A), then watershould be added to a compound of Formula (10A) in order achieve itshydrolysis and the subsequent formation of a compound of Formula (11A).

As explained above, the chemistry used to convert a compound of Formula(10A) to a compound of Formula (11A) according to Step (4B) may begenerally used to prepare a composition comprising compounds (11A) and(11B), having an (11A):(11B) molar percent ratio of from 100:0 to 0:100,from a composition comprising compounds (10A) and (10B), having a(10A):(10B) molar percent ratio of from 100:0 to 0:100, wherein thecompounds (11A) and (11B) have the Formulae (11A) and (11B),respectively. In addition, under aqueous reaction conditions, acomposition comprising compounds (6A) and (6B) and having a (6A):(6B)molar percent ratio of from 100:0 to 0:100 may be converted to acomposition comprising compounds (11A) and (11B), having an (11A):(11B)molar percent ratio of from 100:0 to 0:100, without need to isolate orpurify the intermediate compounds (10A) or (10B). ##STR15## In formulae11A and 11B, R₂, R₃, R₄, R₅, A, B, D, G, Z and R₁₁ are as definedhereinabove.

The invention also provides for the conversion of a compound of Formula(11A) to a compound of Formulas (12A), and the subsequent conversion ofa compound of Formula (12A) to a compound of Formula (13A). It is notnecessary to isolate the compound of Formula (12A). Indeed, a compoundof Formula (11A) is preferably reacted under conditions that immediatelyconvert a compound of Formula (12A) to a compound of Formula (13A) sothat a compound of Formula (12A) is not isolated. Furthermore, it ispreferred to carry out the conversion of a compound of Formula (6A) to acompound of Formula (13A) in a single reaction kettle, without isolationof any of the intermediate compounds (10A), (12A) or (12A). While eitherof compounds of Formula (11A) or (12A) could be isolated and purified,these isolation steps are not preferred because they increase theexpense of preparing the endothelin receptor antagonists of interest.

Thus, according to a preferred process, the product mixture containing acompound of Formula (11A) as prepared according to Step (4B), which alsocontains water and base, is extracted with an organic hydrophobicsolvent. Suitable organic hydrophobic solvents include aliphatic andaromatic hydrocarbons and chlorohydrocarbons, and the like. Thepreferred organic hydrophobic solvent, preferably has a boiling point ofless than about 150° C. Xylenes, toluene and chlorobenzene are preferredsolvents for the extraction step, with toluene being particularlypreferred.

Alcohol is a preferred solvent for Step (5B), and alcohol is also asuitable solvent for Step (5A). Thus, the invention provides for theorganic hydrophobic solvent to be replaced with an alcohol solvent.Suitable alcohol solvents have the Formula HO--R₁₃, wherein R₁₃ is C₁₋₅alkyl. Suitable solvents include methanol, ethanol, n-propanol andisopropanol. The alcohol solvent is preferably a primary alcohol, and ismore preferably methanol or ethanol.

In order to replace toluene, or whatever organic hydrophobic solvent hasbeen used for the extraction of Step (5A), with an alcohol solvent, thesolution of the compound of Formula (11A) in an organic hydrophobicsolvent is concentrated using distillation, and the compound of Formula(11A) redissolved in alcohol. A preferred alcohol solvent is methanol,i.e., R₁₃ is methyl. Some Bronsted acid is added to the alcohol solutionof the compound of Formula (11A) in order to effect cleavage of the arylether --OR₂ group, according to Step (5A). Suitable and preferredBronsted acids are the same as those set forth above in connection withScheme 3, Route (A), Step (1). Also, the suitable and preferredtemperatures at which the compound of Formula (11A) is converted to acompound of Formula (12A) are the same as the suitable and preferredtemperature set forth in connection with Scheme 3, Route (A), Step (1).

The preferred concentration of acid used in Step (5A), and optionallyStep (5B), is about 20 mL to about 200 mL per about 0.05 to about 1.0mol of the aryl ether compound of Formula (11A). Preferably, the ratioof acid to the aryl ether compound of Formula (11A) is about 30 mL toabout 100 mL acid per 0.1 to about 0.5 mol of aryl ether, and morepreferably is about 40 mL to about 60 mL acid per 0.1 to about 0.15 molaryl ether.

In order to convert the compound of Formula (12A) to a compound ofFormula (13A), the reaction mixture from Step (5A) is taken to asufficient temperature to effect the conversion. Preferably, thetemperature ranges from about 20° C. to about 80° C., more preferablyabout 40° C. to about 80° C., and most preferably about 50° C. to about70° C. It is typically the case that Step (5B) should be conducted at ahigher temperature than is necessary for Step (5A), in order to achievea commercially desirable rate for the conversion of a compound ofFormula (11A) to a compound of Formula (13A).

As explained above, the chemistry of Step (5A), used to convert acompound of Formula (11A) to a compound of Formula (12A), can alsogenerally be used to prepare a composition comprising compounds (12A)and (12B), having a (12A):(12B) molar percent ratio of from 100:0 to0:100, from a composition comprising compounds (11A) and (11B), havingan (11A):(11B) molar percent ratio of from 100:0 to 0:100, wherein thecompounds (12A) and (12B) have the Formulae (12A) and (12B),respectively. ##STR16## In formulae 12A and 12B, R₃, R₄, R₅, A, B, G, D,Z and R₁₁ are as defined hereinabove.

The composition of compounds having Formulae (12A) or (12B) is convertedto a composition of compounds having the Formulae (13A) or (13B),respectively. Furthermore, under the reaction conditions described inaccordance with Scheme 4, the compounds of Formulae (11A) and (11B) canbe converted directly to compounds of Formulas (13A) and (13B), withoutthe isolation or purification of any (12A) or (12B) compounds. Thecompounds (13A) and (13B) have the Formulae (13A) and (13B),respectively. ##STR17## In Formulae 13A and 13B, R₃, R₄, R₅, A, B, G, D,Z, R₁₁, and R₁₃ are as defined hereinabove.

It is preferred to conduct Steps 4A, 4B, 5A and 5B (as outlined inScheme 4), in a single reaction flask, without having isolated orpurified any of the compounds of Formulae (10A), (11A) or (12A) bydistillation, chromatography or the like. This can be accomplished bytreating a compound of Formula (6A) with base and water in a suitablesolvent to provide a compound of Formula (11A), then neutralizing thebase with acid and treating the compound of Formula (11A) with acid inthe presence of an alcohol solvent. Thus, according to the chemistrydetailed above, and without any intermediate purification steps, acomposition comprising compounds (6A) and (6B), having a (6A):(6B) molarpercent ratio of from 100:0 to 0:100, can be converted to a compositioncomprising compounds (13A) and (13B), having a (13A):(13B) molar percentratio of from 100:0 to 0:100.

With the compound of Formula (13A) in hand, Step (6) is an alkylationreaction of the phenolic --OH group formed in Step (5A). Thus, in Step(6), the compound of Formula (13A) is treated with an alkylating agentin the presence of a base. The reaction conditions for Step (6) areessentially the same as the reaction conditions that were describedabove in connection with Step (2), which was also an alkylation reactionof a phenolic compound. Preferred alkylating agents are ethylenecarbonate and methyl bromoacetate.

Alkylation of a compound of Formula (13A) affords an aryl ether ofFormula (14A). Thus, as explained above, the alkylation chemistry usedto convert a compound of Formula (13A) to a compound of Formula (14A)according to Step (6) may be generally used to prepare a compositioncomprising compounds (14A) and (14B), having an (14A):(14B) molarpercent ratio of from 100:0 to 0:100, from a composition comprisingcompounds (13A) and (13B), having a (13A):(13B) molar percent ratio offrom 100:0 to 0:100, wherein the compounds (14A) and (14B) have theFormulae (14A) and (14B), respectively. ##STR18## In Formulae 14A and14B, R₃, R₄, R₅, R₆, R₁₁, R₁₂, R₁₃, A, B, D, G and Z are as definedhereinabove.

The invention thus provides a one-pot process for preparing acomposition comprising compounds (14A) and (14B) with a (14A):(14B)molar percent ratio of 100:0 to 0:100. The preferred one-pot processselects a composition comprising compounds (6A) and (6B) with a(6A):(6B) molar percent ratio of 100:0 to 0:100; wherein the compounds(6A), (6B), (14A) and (14B) have the Formulae (6A), (6B), (14A) and(14B), as set forth above. The selected composition is then treated withbase to afford epimerization of the carboxylate ester at position 2. Thethus formed epimerized product is treated with aqueous base to saponifythe carboxylate ester at position 2 and afford a carboxylic acid orsalt. The thus saponified product is then treated with acid to achievecleavage of the --OR₂ group and thereby afford a compound with aphenolic --OH group. The thus formed phenolic compound is treated with aC₁₋₅ monohydric compound of Formula R₁₃ --OH, in the presence of acid toafford esterification of the carboxylic acid group at position 2.Finally, the thus formed esterified product is treated with base and analkylating agent to afford a composition comprising compounds (14A) and(14B).

According to a more preferred one-pot process for preparing compounds ofFormulae (14A) and (14B), the selected composition according to theprevious paragraph is treated with lithium hydroxide in the presence oftetrahydrofuran, methanol and water to afford an epimerized andsaponified product of Formulae (11A&B), which is then treated withhydrochloric acid and methanol to afford an esterified phenolic compoundof Formulae (13A&B), which is then treated with potassium carbonate andan alkylating agent such as ethylene carbonate or L-(CH₂)_(p) CO₂ R₁₃,to afford a composition comprising compounds (14A&B).

According to a still more preferred one-pot process for preparingcompounds of Formulae (14A) and (14B), the selected compositioncomprises the compound (6A) which is methyl-(1S, 2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)-4-methoxyphenyl]-5-propoxyindane-2-carboxylateand compound (6B) which is methyl-(1R, 2R,3R)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)4methoxyphenyl]-5-propoxyindane-2-carboxylate, and the (6A):(6B) molarpercent ratio is preferably about (100-95):(0-5) or about(0-5):(100-95).

In an embodiment of the present invention, the compound of Formula (14A)is saponified according to Step 7 to provide an endothelin receptorantagonist of Formula (7A). The saponification of Step 7 is analogous tothe saponification of Step 3 in Route (A), and thus will not bediscussed in detail. As explained above, the chemistry used to convert acompound of Formula (14A) to a compound of Formula (7A) according toStep 7 may be generally used to prepare a composition comprisingcompounds (7A) and (7B), having a (7A):(7B) molar percent ratio of from100:0 to 0:100, from a composition comprising compounds (14A) and (14B),having a (14A):(14B) molar percent ratio of from 100:0 to 0:100.

Preferably, in the chemistry outlined above for Route (B), the startingmaterial compositions are significantly enriched in one of thediastereomerically-related compounds of Formulae (6A&B), (20A&B),(11A&B), (12A&B), (13A&B) or (14A&B). The term "significantly enriched"has the same meaning as set forth above in connection with the compoundsformed and used in Route (A).

According to Route B, and as explained above, the invention provides forcompounds of Formulae (10A&B), (11A&B), (12A&B), (13A&B) and (14A&B),where compounds of Formulae (14A&B) may be converted to endothelinreceptor antagonists of Formulae (7A&B). The invention thus provides forcompositions comprising diastereomerically-related compounds (15A) and(15B), having the Formulas (15A) and (15B) respectively, which encompassthe compounds of Formulae (10A&B), (11A&B), (12A&B), (13A&B) and(14A&B).

The composition of compounds (15A) and (15B) have a (15A):(15B) molarpercent ratio of from 100:0 to 0:100. Preferably, the compositioncontains one of the compounds (15A) or (15B) in excess, and morepreferably has a (15A):(15B) molar percent ratio of about(100-75):(3-25) or about (0-25):(100-75), and still more preferably hasa (15A):(15B) molar percent ratio of about (100-90):(0-10) or about(0-10):(100-90), and yet still more preferably has a (15A):(15B) molarpercent ratio of about (100-95):(6-5) or about (0-5):(100-95).Compositions having one of the compounds (15A) or (15B) in essentiallyisomerically pure form are most preferred, where isomerically pure formmeans that at least about 98%, and preferably at least about 99% of thecomposition is a single one of (15A) or (15B).

Compounds (15A) and (15B) have the Formulae (15A) and (15B)respectively, ##STR19## or are pharmaceutically acceptable saltsthereof. In Formulae 15A and 15B, R₂, R₃, R₄, R₅, A, B, D, G, Z, R₁₁,are as defined hereinabove,

R₁₂ is --(CH₂)₂ OH or --(CH₂)_(p) CO₂ R₁₃ where p is an integer from 1to 3;

R₁₃ is hydrogen or C₁₋₅ alkyl;

R₁₄ is H, R₂, or R₁₂ ;

R₁₅ is H, R₁₀ or R₁₃ ;

provided that when R₁₅ is H, R₁₄ is H or R₂.

Particularly preferred compounds of Formula (15A) are the following:methyl-(1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)4-methoxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylate;(1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)4-methoxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylicacid; (1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid; methyl-(1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate;and methyl-(1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylate.

Thus utilizing the techniques described herein, and as examplified inthe following examples, (+)(1S, 2R, 3S)3-(2-carboxymethyoxy-4-methoxyphenyl)-1-(3,4-metylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and(+)(1S, 2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmacuetically acceptable salts thereof, having the chemicalstructures 20 and 21, respectively depicted hereinbelow, ##STR20## aresynthesized in an efficient and economical manner. For example, anexemplary procedure for synthesizing Compound 20 and 21, is as followsstarting from 2-Bromo-3-hydroxyanisole (a compound of Formula 1 whereinR₁ is bromo, R₃ and R₅ are hydrogen and R₄ is 4-methoxy). This isreacted with base followed by reaction with2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyl chloride to form acompound of Formula 3 wherein R₂ is2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyl, and R₁, R₃, R₄ and R₅are as defined hereinabove. The compound of Formula 3 is converted tothe Grignard reagent which is reacted with a compound of Formula 4having structure 22 ##STR21## to provide a compound of structure 5A and5B (Structures 23 and 24). ##STR22##

Utilizing the crystallization techniques described hereinabove, compound23 is isolated and hydrogenated under the reaction conditions describedherein to provide a compound of Formula 6A (25). ##STR23##

To synthesize compound 20, in one embodiment, 25 is reacted with acidfollowed by alkylation with L--(CH₂)pCO₂ R₁₃ such as methylbromoacetate, (wherein L is Bromo, p is 1, and R₃ is CH₃) in base, andthen the product thereof is reacted with aqueous base, such as aqueoushydroxide. On the other hand, compound 21 is synthesized, as anotherembodiment by reacting 25 with acid then by alkylating with ethylenecarbonate in the presence of base, e.g., potassium carbonate and thenreacting the product thereof with aqueous base, in accordance with theprocedure described herein.

Thus the process of the present invention forms compounds of Formulae 7Aand 7B as well as the precursors thereof as substantially purecompounds. In addition, they are substantially enantiomerically pure anddiasteromerically pure. By substantially, it is meant that the purify isat least 75% and more preferably at least 90%, and even more preferablyat least 95% pure, and most preferably 98% pure in the categoriesemphasized.

The invention will now be illustrated in more detail by the followingnon-limiting examples, which demonstrate the advantageous properties ofthe present invention. Parts and percentages are by weight unlessindicated otherwise.

EXAMPLE 1

Preparation of 2-bromo-5-methoxyphenyl2,3:5.&di-O-isopropylidene-a-D-mannofuranoside with potassium t-butoxidein DME-THF

To a stirred solution of 2-bromo-5-methoxyphenol (420 g, 2.07 mol) in2.5 L of 1,2-dimethoxyethane under a nitrogen atmosphere at 0° C. wasadded a 1 M solution of potassium t-butoxide in tetrahydrofuran (3.10 L,3.1 mol). The solution was stirred for 15 minutes then2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyl chloride (810 g, 2.91mol) in 1.68 L of 1,2-dimethoxyethane was added over 15 minutes. Thereaction mixture was refluxed for 90 minutes. The reaction was quenchedwith 420 mL of water, then 5.0 L of toluene and 10.1 L of a 2.5 Naqueous sodium hydroxide solution was added and the reaction was stirredfor 5 minutes. The aqueous layer was separated and the organic layer waswashed twice with 2.5 L portions of 2.5 N aqueous sodium hydroxidesolution. The organic solution was concentrated in vacuo to 50% of it'soriginal volume and 500 g of Florisil™ was added. The solution wasstirred for 25 minutes then filtered through a pad of 1.0 kg of Aluminumoxide and 420 g of Florisil™. The filter pad was washed with 6 L of 10%ethyl acetate in toluene. The filtrate was concentrated to approximately1.5 L which weighed 1247.9 g. The concentrate was assayed vs. areference sample of the title compound. HPLC wt/wt assay indicated 68.0%wt/wt which represents 848.6 g of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside, (92.1% yield,corrected). An analytical sample was prepared by flash columnchromatography on silica gel eluting with ethyl acetate:hexane 20:80.

¹ H NMR (CDCl₃), d (ppm ) 7.42 (d, 1H, J=8.8 Hz), 6.52 (dd, 1H, J=2.7and 8.8 Hz), 5.63 (S, 1H), 4.98 (m, 2H), 4.45 (m, 1H), 4.2 (dd, 1H,J=2.9 and 7.9 Hz), 4.11 (1/2d_(AB), 1H, J_(AB) =8.75 and 6.3 Hz), 4.01(1/2d_(AB), 1H, J_(AB) =8.75 Hz and 6.3 Hz), 3.79 (s, 3H), 1.43 (m, 12H). Anal. calc. for C 19 H₂₅ BrO_(7;) C; 51.24, H: 5.66, Found; C:51.27, H: 5.72. m.p. 67-68° C.

EXAMPLE 2

Preparation of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside with potassiumt-butoxide in DME-THF with isolation.

To a stirred solution of 2-bromo-5-methoxyphenol (500.0 g, 2.46 mol) in3.00 L of 1,2-dimethoxyethane under a nitrogen atmosphere at 25° C. wasadded 1 M solution of potassium t-butoxide in tetrahydrofuran (3.69 L,3.69 mol) at such a rate as to keep the temperature below 35° C. Thesolution was stirred for 15 minutes then2,3:5,6di-O-isopropylidene-a-D-mannofuranose (960.3 g, 3.45 mol) in 2.00L of 1,2-dimethoxyethane was added over 20 minutes. The reaction mixturewas heated to reflux and held at reflux for 2 hours. The reaction wascooled to 25-27° C. and quenched with 250 mL of water, then 1.75 mL oftoluene and 1.50 L of a 2.5 N aqueous sodium hydroxide solution wereadded and the reaction was stirred for 5 minutes. The aqueous layer wasseparated and the organic layer was washed twice with 1.50 L portions of2.5 N aqueous sodium hydroxide solution. The organic solution was thenwashed with 1.50 L of saturated sodium chloride solution and 1.5 L ofwater. The organic layer was concentrated to approximately 2.0 L undervacuum and filtered. Isopropanol (1 L) was added and the solution wasconcentrated to a volume of approximately 1.0 L. An additional 1.0 L ofisopropanol was added the solution was again concentrated to a volume ofapproximately 1.0 L. Isopropanol (1 L) was added and the solution wascooled to 0° C. and seed crystals of the title compound added. Thesolution was stirred at 0° C. for 16 hours then filtered and washed withisopropanol (2×500 mL). The product was dried at 0.1 Torr at 25° C. for72 hours to afford 878.3 g of the title compound as a white solid (80.2%yield).

¹ H NMR (CDCl₃), d (ppm) 7.42 (d, 1H, J=8.8 Hz), 6.52 (dd, 1H, J=2.7 and8.8 Hz), 5.63 (S, 1H), 4.98 (m, 2H), 4.45 (m, 1H), 4.2 (dd, 1H, J=2.9and 7.9 Hz), 4.11 (1/2d_(AB), 1H, J_(AB) =8.75 and 6.3 Hz), 4.01(1/2d_(AB), 1H, J_(AB) =8.75 Hz and 6.3 Hz), 3.79 (s, 3H), 1.43 (m, 12H). Anal. calc. for C 19 H₂₅ BrO_(7;) C; 51.24, H: 5.66, Found; C:51.27, H: 5.72. m.p. 67-68° C.

EXAMPLE 3

Preparation of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside with NaH in DME

To a stirred suspension of NaH (3 g, 60% dispersion in mineral oil, 75mmol) in 50 mL of dimethoxy ethane (DME) was added a solution of2-bromo-5-methoxyphenol (10.15 g, 50 mmol) in 50 mL of DME at 20-25° C.under an atmosphere of nitrogen. After the addition of2-bromo-5-methoxyphenol, the reaction was stirred for 10 minutes andthen a solution of 2,3:5,6-di-O-isopropylidene-a-D-mannofuranosylchloride (16.7 g, 60 mmol) in 150 mL of DME was added at 40-45° C. Afterthe addition, the reaction mixture was heated to 80-85° C. and kept atthis temperature for approximately 5 hours. The reaction was quenchedwith 5 mL of water and concentrated in vacuo. To the concentrate, 300 mLof t-butyl methyl ether was added followed by 150 mL of water and theresulting solution stirred for 5 minutes before the organic phase wasseparated. The aqueous layer was back-extracted with 100 mL of t-butylmethyl ether. The combined organics were washed with 10% aqueous NaOHsolution (2×120 mL), followed by 200 mL of brine. The organic solutionwas then dried over MgSO₄, filtered and treated with activated carbon(Darco) by heating to 55° C. for 5 minutes. After removing the activatedcarbon by filtration through Celite, the filtrate was concentrated invacuo. The concentrate was taken up into 40 mL of CH₂ Cl₂ and passedthrough a pad of basic aluminum oxide by eluting with 600 mL of 20%EtOAc in hexane. The elute was concentrated in vacuo to afford 15.7 g(70.5%) of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside as a light yellow oil.The HPLC analysis (CH₃ CN/H₂ O=65/35, 1.0 mLrnmin, Inertsil C18, 5m, 4.6mm×30 mm, l=220 nm) indicated 96% (PAR) of title compound together with3% (PAR) of the b-anomer, 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-b-D-mannofuranoside.

EXAMPLE 4

Preparation of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside and2-bromo-5-methoxyphenyl 2,3:5,6-di-O-isopropylidene-b-D-mannofuranosidewith DBU as the base

In a similar manner to that described above 2-bromo-5-methoxyphenol(0.99 g, 4.67 mmol) in 15 mL of toluene, 0.73 g (4.79 mmol) of1,8-diazobicylclo[5,4,0]undec-7-ene (DBU) and2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyl chloride (1.3 g, 4.87mmol) were heated at 100° C. for approximately 20 hours to afford amixture of the title compounds in a ratio of 3:2 (as judged by HPLC peakarea ratio). The reaction was worked up in a similar manner to thatdescribed above and the title compounds isolated by columnchromatoghaphy eluting with ethyl acatate and hexane.

¹ H NMR (CDCl₃) for 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-b-D-mannofuranoside, d (ppm) 7.40 (d, 1H,J=8.7 Hz), 6.7 (d, 1H, J=2.8 Hz), 6.5 (dd, 1H, J=8.8 and 2.7 Hz), 5.3(d, 1H, J=3.7 Hz), 4.8 (m, 2H), 4.6-4.5 (m, 1H), 4. 1-1.0 (m, 2H), 3.9(q, 1H, 3J632 3.8 and 7.8 Hz) 3.8 (s, 3H), 1.6 (s, 3H), 1.45 (s, 3H),1.43 (s, 3H), 1.38 (s, 3H).

EXAMPLE 5

Preparation of 2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy)chlorobenzene.

To a stirred solution of 2-chlorophenol (1.24 g, 1.0 mL, 9.6 mmol) in 12mL of 1,2-dimethoxyethane under a nitrogen atmosphere at 3° C. was addeda 1 M solution of potassium t-butoxide in hexane (14.0 mL, 14 mmol). Thesolution was stirred for 5 minutes then2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyl chloride (3.30 g, 12mmol) in 10 mL of 1,2-dimethoxyethane was added over 5 minutes. Thereaction mixture was refluxed for 90 minutes. The reaction was quenchedwith 2 mL of water, then 50 mL of ethyl acetate and 40 mL of a 2.5 Naqueous sodium hydroxide solution were added and the reaction wasstirred for 5 minutes. The aqueous layer was separated and backextracted with 50 mL of ethyl acetate. The organic solution wasconcentrated in vacuo to a yellow-brown oil. This oil was purified bysilica gel flash column chromatography (ethyl acetate/hexane=1/10) toafford 2.88 g (79%) of the title compound as a white crystalline solid.An analytical sample was prepared by preparative chromatography usingreverse phase plates purchased from Chem Dynamics (86-7827-70, RP-18/UV254, 1 mm thickness) developing with acetonitrile/water (60:40).

¹ H NMR (CDCl₃), d (ppm) 7.39 (dd, 1H, J=1.2, 8 Hz), 7.28 (2xdd, 2H,J=1.3, 8.4 Hz), 7.00 (ddd, 1H, J=1.0, 6.9, 8, Hz), 5.63 (s, 1H), 4.95(m, 2H), 4.43 (m, 1H), 4.18 (dd, 1H, J=2.9, 7.9 Hz), 4.09 (dd, 1H,J=6.2, 8.7 Hz), 3.98 (dd, 1H, J=4.2, 8.7 Hz), 1.43 (m, 12 H).

Anal. calc. for C₁₈ H₂₃ O₆ Cl; C: 58.29, H: 6.25, Found; C: 58.19, H:6.13.

EXAMPLE 6

Preparation of2.6-Dimethyl-4-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy)bromobenzene.

To a stirred solution of 4-bromo-3,5-dimethylphenol (2.01 g, 10 mmol) in12 mL of 1,2-dimethoxyethane under a nitrogen atmosphere at 0° C. wasadded a 1 M solution of potassium t-butoxide in hexane (15.0 mL, 15mmol). The solution was stirred for 5 minutes then2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyl chloride (3.90 g, 14mmol) in 8 mL of 1,2-dimethoxyethane was added over 5 minutes. Thereaction mixture was refluxed for 90 minutes. The reaction was quenchedwith 2 mL of water, then 25 mL of toluene and 50 mL of a 2.5 N aqueoussodium hydroxide solution were added and the reaction was stirred for 5minutes. The aqueous layer was separated and the organic layer waswashed with 2×25 mL portions of 2.5 N aqueous sodium hydroxide solution.The organic solution was concentrated in vacuo to 50% of it's originalvolume and 5 g of Florisil™ was added. The solution was stirred 10minutes then filtered through a pad of 10 g of Aluminum oxide and 5 g ofFlorisil™. The filter pad was washed with 100 mL of 10% ethyl acetate intoluene. The filtrate was concentrated to afford 4.71 g of the titlecompound. An analytical sample was prepared by preparativechromatography using reverse phase plates purchased from Chem Dynamics(8&7827-70, RP-18/UV 254, 1 mm thickness) developing withacetonitrile/water (60:40).

¹ H NMR (CDCl₃), d (ppm) 6.75 (s, 1H), 5.60 (s, 1H), 4.90 (m, 1H), 4.85(m, 1H), 4.45 (m, 1H), 4.15 (m, 1H), 4.10 (m, 1H), 4.00 (m, 1H), 2.35(s, 6 H), 1.45 (m, 12H).

Anal. calc. for C₂₀ H₂₇ BrO₆ ; C; 54.18, H: 6.14, Found; C: 54.46, H:5.78.

EXAMPLE 7

Preparation of (R) and(S)-methyl-3-(3,4-methylenedioxyphenyl-1-hydroxy-1-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate.

Method 1: Halogen Metal Exchange followed by transmetallation

To a stirred solution of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside (303.8 g, 68% wt/wtassay in toluene, 463.9 mmol) in 1.7 L of THF under a nitrogenatmosphere at -75° C. was added 185 mL of n-BuLi (24% solution inhexane, nominally 2.6 M) over 30 minutes. The solution was stirred for 5minutes then approximately 0.1 mL of this solution was taken for HPLCanalysis to ensure complete metal-halogen exchange. With moderateagitation, MgBr₂.Et₂ O (180 g, 697.1 mmol) was added at -78 to -75° C.After the addition of MgBr₂.Et₂ O, the resulting suspension was warmedto 22-25° C. over 80 minutes so that the reaction mixture was a clearsolution. This solution was stirred for another 2 hours before it wascooled back to -78° C. To the slightly cloudy solution at -78° C., asolution of methyl 3-(1,3-benzodioxol-5-yl)-1-oxo-propoxy-2H-indene-2-carboxylate (110 g, 297 mmol) in 1.1 L of THF) was addedslowly so that the internal temperature did not go above -72° C. Thereaction mixture was stirred for 5 minutes after the addition wascomplete and a small amount of the mixture removed for HPLC analysis.The ratio of two diastereomeric products was 88:12 with the (R)-isomeras the major one by HPLC (PAR). The reaction was quenched with 100 mL of20% aqueous solution of NH₄ Cl at about -72° C. and warmed to 22-25° C.The resulting mixture was concentrated from 3.5 L to 3.0 L bydistillation. After concentration, 1 L of water was added and themixture was stirred for 5 minutes. The aqueous layer was separated andback extracted with 300 mL of toluene. The organic solution was washedwith 500 mL of water to yield a mixture of crude (R)- and(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate(88 to 12) as a solution in THF and toluene.

Method 2: Direct Grignard Method

To a stirred solution of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-manno-furanoside (0.2 g, 0.45 mmol) inanhydrous tetrahydrofuran (THF) (3 mL) under a nitrogen atmosphere at18° C. was added Mg (0.15 g, 6.25 mmol). To this mixture,1,2-dibromoethane (50 mL, 0.59 mmol) was added. The temperature of thismixture went up from 18° C. to 23° C. over approximately 10 minutes. Atthis time, a solution of 2-bromo-5-methoxyphenyl2,3:5,6-di-O-isopropylidene-a-D-mannofuranoside (1.8 g, 4.04 mmol) inanhydrous THF (12 mL) was added slowly at 25-31° C. over 10 minutes.After the addition, the Grignard reagent was stirred for 30 minutes andchecked by HPLC. This solution was then added via a cannular into asuspension of methyl3-(1,3-benzodioxol-5-yl)-1-oxo-6-propoxy-1H-indene-2-carboxylate (1.07g, 2.92 mmol) in anhydrous THF (10 mL) at between -70 and -65° C. over10 minutes. After this addition, the reaction mixture was warmed from-70° C. to -5° C. over approximately 15 minutes and a small aliquot wastaken for HPLC analysis. The ratio of the two diastereomeric productswas determined to be 85 to 15 with the (R)-isomer as the major one byHPLC (PAR). The reaction mixture was quenched with aqueous NH₄ Clsolution (17%, 1.5 mL). The quenched mixture was evaporated underreduced pressure then taken up into EtOAc (15 mL). This organic mixturewas washed with aqueous citric acid solution (3%, 25 mL), followed by H₂O (2×30 mL) to neutral pH. From this crude eaction mixture,(R)-methyl-3-(3,4-methylenedioxyphenyl)-1hydroxy2-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyl-oxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylatecould be isolated as described below.

EXAMPLE 8

Isolation of(R)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate.

A mixture of (R)- and(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylatepreprared as described above (either by Method 1 or 2), ratio 88:12 R toS, in THF and toluene (3500 mL) was concentrated in vacuo at 25-50° C.to a volume of approximately 300-350 mL. To this concentrate, 550 mL ofn-butanol was added. The resulting red-brown solution was concentratedin vacuo at 50-57° C. to a volume of 400-450 mL. The concentrate wascooled and 100 mL of water was added. The resulting slurry was cooled to30-35° C. before it was seeded. After seeding, the slurry was stirred at20-25° C. for 20 hours, and the desired (R)-isomer precipitated outslowly during this stir period. The product was isolated by vacuumfiltration and rinsed with 2×110 mL portions of n-butanol followed by2×110 mL portions of hexane to yield after drying, 152 g (69% yield) ofthe title compound. Analysis indicated 98.4% wt/wt and 99.5% d.e. Ananalytical sample was prepared by recrystallization fromn-butanol/water.

¹ H NMR (CDCl₃), d (ppm) 7.96 (1H, d, J=8.7 Hz), 7.19 (1H, d, J=8.4 Hz),7.08-7.03 (2H, m), 6.92 (1H, d, J=7.9 Hz), 6.78 (1H, dd, J=3.3, 8.4 Hz),6.72 (1H, d, J=2.3 Hz), 6.69 (1H, dd, J=2.6, 8.7 Hz), 6.55 (2H, d, J=2.3Hz), 6.04 (2H, AB, J=6.1 Hz), 5.46 (1H, s), 4.41-4.37 (2H, t), 4.22-4.18(2H, m), 3.97-3.82 (2H, m), 3.79 (3H, s), 3.68 (1H, qt, J=4.8, 8.7 Hz),3.56 (3H, s), 2.90 (1H, qt, J=4.7, 8.0 Hz), 1.72 (2H, qt, J=6.9, 14.1Hz), 1.41 (3H, s), 1.33 (3H, s), 1.30 (3H, s), 1.15 (3H, s), 0.97 (3H,t, J=7.5 Hz). Anal. calc. for C₄₀ H₄₄ O₁₃ ; C: 65.56, H: 6.05, Found; C:65.46, H: 6.02.

EXAMPLE 9

Isolation of(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-2-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylate.

(S)-methyl-3-(3,4-methylenedioxyphenyl)-2-hydroxy-2-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylatewas isolated by reverse phase preparative chromatography on a WatersPrep 500 eluting with ethyl acetate and hexane (85:15) as the eluents.

¹ H NMR (CDCl₃), d (ppm) 7.96 (1H, d, J=8.7 Hz), 7.25 (1H, m), 7.03-7.0(2H, m), 6.89 (1H, dd, J=7.7 and 0.9 Hz), 6.81-6.74 (m, 2H), 6.7 (1H,dd, J=8.6 and 2.5 Hz), 6.59 (2H, d, J=2.5 Hz), 6.04 (2H, s), 5.16 (1H,s), 4.5 (1H, dd, J=5. 8 and 3.7 Hz), 4.3-4.21 (2H, m), 3.9-3.8 (6H, m),3.57 (3H, s), 1.75 (2H, dd, J=6.7 and 4.0 Hz), 1.39 (3H, s), 1.38 (3H,s), 1.34 (3H, s), 1.24 (3H, s), 0.98 (3H, s).

EXAMPLE 10

Preparation of methyl-(2S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-(prop-1-yloxy)indane-2-carboxylate

A 5 gallon Hastelloy-C reactor and all necessary equipment was inspectedfor cleanliness and dryness. The vessel was pressure tested to 100 psito determine the leak rate. When an acceptable leak rate wasestablished, the reactor was flushed with nitrogen and residual oxygenlevels determined. When acceptable levels of oxygen were detected, thevessel was charged with 12 L of ethyl acetate, 1.26 kg (97.9%, 1.68 mol)of(R)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylateand 500 g of 15% Pd/C 1910 (approximately 50% water wet) purchased fromPrecious Metals Corporation. The vessel was sealed, then pressurised toapproximately 100 psi with nitrogen, then vented to the atmosphere. Thisprocedure was repeated an additional 2 times. After the third cycle, thereactor leak rate was monitored for approximately 5 minutes. When asatisfactory leak rate was established, the nitrogen was vented to theatmosphere and the vessel pressurised to 100 psi with hydrogen. Thehydrogen was released to the atmosphere and the cycle repeated anadditional 2 times. After the third cycle, the vessel was re-pressurisedwith hydrogen to approximately 100 psi and the agitator started. Theagitator was set at 700-750 rpm. The progress of the reaction wasmonitored by in-process HPLC analysis and by the recorded hydrogenuptake. The reaction was deemed complete after 4 hours at ambienttemperature and 100 psi hydrogen pressure after a theoretical uptake ofhydrogen had been recorded (typically pressures of between 80-100 psihydrogen pressure are optimal). The hydrogen was vented to theatmosphere and the vessel purged 3 times with nitrogen. After eachpurge, the nitrogen was vented to the atmosphere. The contents of thevessel were drained into a clean poly drum and the reactor rinsed with 4L of ethyl acetate. The combined organics were filtered throughapproximately 500 g of celite, washing with ethyl acetate to yield 27 Lof an ethyl acetate solution of crude SB 223222, 80.7% PAR by HPLC.

EXAMPLE 11

Isolation of methyl-(1S,2S,3S)-2-(3,4-methylenedioxyphenyl)3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-(prop-1-yloxyl)indane-2-carboxylate

A glass-lined 10 gallon reactor, and all necessary equipment wasinspected for cleanliness and dryness. Via filtration through a 1 micronfilter, 54 L of a solution of crudemethyl-(1S,2S,3S)-2-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylatewas added. At atmospheric pressure, the solution was concentrated bydistillation at atmospheric pressure to a final volume of approximately18 L. Ethanol (24 L) was added to the concentrate and the resultingmixture concentrated down at atmospheric pressure to a volume of 18-20L. Additional ethanol (24 L) was added resulting in the precipitation ofthe title compound. The slurry was concentrated again at atmosphericpressure to a volume of 24 L before the addition a third ethanol chase(24 L). The resulting slurry was concentrated at atmospheric pressure toa final volume of approximately 24 L, then allowed to cool to ambienttemperature overnight. After stirring for approximately 12-16 hours atambient temperature, the slurry was cooled to 0-5° C. and stirred atthis temperature for approximately 3 hours before isolation of theproduct by centrifugation. The solids were washed with ethanol (12 L of200 proof chilled to 05° C.) then dried to constant weight to yield 1.90kg (75.1% corrected yield) of the title compound as a white crystallinesolid. Analysis indicated >99.9% de by HPLC. [Yields for this conversionare typically in the range 60-80%.]

¹ H NMR (CDCl₃), d 7.32 (1H, d, J=8.6 Hz), 7.08 (1H, q, J=8.3 and 1.2Hz), 6.74-6.89 (6H, m), 6.55 (1H, q, J=8.7 and 2.6 Hz), 5.93 (1H, q,J=2.9 and 1.5 Hz), 5.68 (1H, s), 4.94-5.01 (3H, m), 4.69 (1H, d, J=7.6Hz), 4.44-4.49 (1H, m), 4.22 (1H, q, J=3.5 and 7.6 Hz), 4.13 (1H, q,J=6.3 and 8.7 Hz), 4.04 (1H, q, J=4.6 and 8.7 Hz), 3.90 (2H, t, J=6Hz),3.84 (1H, t, J=8Hz), 3.80 (s, 3H), 2.96 (s, 3H), 1.77-1.82 (m, 2H), 1.54(s, 3H), 1.43 (s, 3H), 1.41 (s, 3H),1.39 (s, 3H), 1.03 (t, 3H, J=7.4Hz).

EXAMPLE 12

Preparation ofmethyl-(1R,2R,3R)-1-3,4-methylenedioxyphenyl-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate

A 100 mL miniclave was charged with 15 mL of ethyl acetate, 15 mL ofethanol (200 proof), 130 mg of(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-[2-(2,3:5,6-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-6-propoxy-1H-indene-2-carboxylateand 64 mg of 10% Pd on Carbon (on a dry basis). The vessel was sealed,then pressurised to approximately 400 psi with nitrogen, then vented tothe atmosphere. This procedure was repeated an additional 2 times. Afterthe third cycle, the reactor leak rate was monitored for approximately 5minutes. When a satisfactory leak rate was established, the nitrogen wasvented to the atmosphere and the vessel pressurised to 100 psi withhydrogen. The hydrogen was released to the atmosphere and the cyclerepeated an additional 2 times. After the third cycle, the vessel wasre-pressurized with hydrogen to approximately 400 psi, the internalcontents warmed to 55° C. and the agitator started. The reaction wasdeemed complete after 24 hours. The hydrogen was vented to theatmosphere and the vessel purged 3 times with nitrogen. After eachpurge, the nitrogen was vented to the atmosphere. The contents of thevessel were drained into a clean container and the reactor rinsed with20 mL of ethyl acetate. The combined organics were filtered throughapproximately 5 g of celite, washing with ethyl acetate to yield afterconcentration the title product. The crude material was purified bycrystallization from methanol to yield 64 mg (50.3%) of the titlecompound as white needles. Analysis indicated >99.9% de by HPLC.

¹ H NMR (CDCl₃), d 7.29 (1H, d, J=8.6 Hz), 7.08 (1H, d, J=8.1 Hz),6.73-6.87 (6H, m), 6.52 (1H, q, J=8.6 and 2.5 Hz), 5.93 (1H, q, J=2.9and 1.5 Hz), 5.69 (1H, s), 4.944.97 (3H, m), 4.71 (1H, d, J=7.7 Hz),4.444.49 (1H, m), 4.124.14 (2H, m), 4.04 (1H, q, J=4.6 and 8.7 Hz), 3.91(2H, t, J=6Hz), 3.84 (1H, t, J=8 Hz), 3.78 (s, 3H), 2.97 (s, 3H),1.77-1.82 (m, 2H), 1.54 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H),1.39 (s,3H), 3.80 (t, 3H, J=7.4 Hz).

EXAMPLE 13

Preparation ofmethyl-(S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate

To a solution ofmethyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate(100 g, 0.139 mol) in THF (900 mL) and methanol (400 mL) was added asolution of lithium hydroxide (29.2 g, 0.695 mol) in water (360 mL). Thereaction mixture was heated to reflux and monitored by HPLC. Thereaction was complete in 2.5 hours. The reaction was cooled to 2025° C.and 1.57 L of toluene and a solution of 100 g of citric acid in 1.5 L ofwater was added. The layers were separated and the aqueous layer wasextracted with 1.57 L of toluene. The combined toluene layers werewashed with 2 portions of 5% aqueous sodium bicarbonate (1.2 L) andconcentrated under reduced pressure to approximately 250 mL. The toluenesolution of (1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylicacid was filtered through Celite and methanol (1000 mL) was added.Concentrated hydrochloric acid (49.5 mL) was added in one portion andthe solution was heated to reflux. The reaction was monitored by HPLCand was complete in approximately 2 hours. The reaction mixture wascooled to 20-25° C. and 100 mL of water and 250 mL of toluene was added.The solution was concentrated under reduced pressure to approximately400 mL. Toluene (750 mL) and water (100 mL) were added, followed by 5%sodium bicarbonate solution (260 mL). The layers were separated and theorganic layer was washed twice with 5% sodium bicarbonate solution(2×260 mL). The organic layer was concentrated to about 200 mL underreduced pressure, toluene (300 mL) was added, then the solution wasfiltered through Celite. The filtrate was concentrated to approximately500 mL to afford approximately a 15-20% solution of methyl-(1S, 2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylatein toluene. The final solution was sampled for assay and found tocontain 14.6% of the desired material. This represents 66.27 g ofproduct (99.6% yield, corrected). A sample was concentrated underreduced pressure for spectral analysis:

¹ H NMR (CDCl₃), d 7.0 (d, 1H), 6.82-6.68 (m, 5 H), 6.58-6.48 (m, 2H),5.95 (d, 2 H), 4.9 (d, l=10.5 Hz, 1 H), 4.40 (d, J=10.5 Hz, 1H), 3.83(m, 2 H), 3.78 (s, 3H), 3.70 (s, 3H), 3.25 (t, J=10.5 Hz, 1H), 1.75 (m,2H), 1.0 (t, 3H) ppm.

EXAMPLE 14

Preparation ofmethyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

A 5 L 3 necked round-bottom flask equipped with an air driven stirrer,reflux condenser and a nitrogen inlet/outlet was charges with 375.0 g(96.1% wt/wt, 501.4 mmol)methyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate,3750 mL of methanol and 37.5 mL of concentrated aqueous HCl. Theresulting slurry was heated to 60-65° C. under an atmosphere of nitrogenover a period of approximately 60 minutes. When at 63° C., an additional37.5 mL of concentrated aqueous HCl was added to the mixture and thesolution maintained within the temperature range of 60-65° C. Theprogress of the reaction was monitored by HPLC. The reaction was deemedto be complete when no starting material was detected. The resultingclear solution was allowed to cool towards ambient temperature over aperiod of approximately 3 hours. When at or below 30° C., 2.0 g of seedcrystals of the title compound were added. The resulting slurry wasstirred at ambient temperature for approximately 18 hours, then cooledto 0-5° C. for an additional 4 hours. The product was isolated byfiltration and washed with 2 portions of methanol (2×500 mL chilled to0-5° C. The isolated methyl-(1S, 2S,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylatewas dried under vacuum (30 in. Hg at 30-35° C.) to constant weight overapproximately 21 hours to yield 213.0 g (88.0 % corrected yield) of thetitle compound. Analysis indicated 98.4% wt/wt and >99.9% ee by HPLC.

EXAMPLE 15

(+) (1S, 2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid ethylene diamine salt (2:1) (Compound)

A 500 mL flask was charged with 150 mL of toluene followed by ethylenecarbonate (29.4 g, 98%, 327 mmol) and 15.9 g (97.4%, 32.6 mmol) ofmethyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-hydroxyphenyl)-5-propoxyindane-2-carboxylate.With moderate agitation at ambient temperature, potassium carbonate(23.1 g, 98%, 163.8 mmol) was added. Under an atmosphere of nitrogen andwith moderate agitation, the contents of the flask were heated toapproximately 112° C. After approximately 3 hours at or around 112° C.,the reaction was cooled to 25-30° C. over a period of 20 minutes, and DIwater (120 mL) was added. The mixture was stirred then the aqueous layerwas separated. The organic phase was concentrated to a gum under reducedpressure then diluted with methanol (50 mL) and tetrahydrofuran (80 mL).A solution of lithium hydroxide monohydrate, 4.5 g (477.8 mmol)dissolved in 50 mL of water was then added. The reaction mixture washeated to reflux (internal temperature 62-65° C.) over approximately 15minutes and maintained at reflux while monitoring the reaction progressby HPLC. The reaction was considered complete when no intermediates weredetected by HPLC analysis. After approximately 60 minutes at reflux thereaction was considered complete and the contents of the flask cooled toambient and the reaction mixture concentrated under reduced pressure.Toluene (150 mL), water (150 mL) followed by citric acid (15 g) was thenadded to the resulting solution and the mixture stirred forapproximately 15 minutes. The bottom aqueous layer was drained and theorganic layer was washed with aqueous brine solution (100 mL). Theorganic layer was drained from the flask, then concentrated in vacuo toafford 16.2 g of the title compound as a foam.

HPLC wt/wt assay indicated 90.5% purity for a corrected yield of 88.8%

An analytical sample could be obtained by recrystallization from2-propanol. Mpt. 125-127° C.

A toluene solution of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (868.8 g @ 11.2% wt/wt, 192.5 mmol) was concentrated under reducedpressure to a volume of approximately 200 mL. Distillation wasdiscontinued and 2-propanol (500 mL) added to the concentrate. Theorganic solution was concentrated again under reduced pressure to avolume of approximately 200 mL. Distillation was discontinued and2-propanol (500 mL) added to the concentrate. The resulting solution in2-propanol was allowed to stir at ambient temperature for approximately15 minutes to obtain a homogeneous mixture then diluted with anadditional 1000 mL of 2-propanol. The resulting solution was heated toapproximately 60° C. over a period of 15-20 minutes under a gentle purgeof nitrogen. Heating was discontinued and ethylene diamine (11.6 g,99.5+%, 192.5 mmol) was added. The reaction mixture was cooled to 30-35°C. over a period of 4 hours. As the solution cooled to 57° C.,precipitation of the title compound occurred. The resulting slurry wasstirred at ambient temperature for approximately 12 hours then cooled to0° C. an additional 3 hours before isolation of the title compound viafiltration. The product was washed with 3 portions of 2-propanol (300mL) followed by hexane's (600 mL) chilled to 0-5° C. The product wasdried in the vacuum oven for approximately 16 hours at 20-25° C. toafford 91.6 (87%) of the title compound.

Anal Calcd. for C₃₀ H₃₄ NO₈ C, 67.15; H, 6.39; N, 2.61. Found, C, 67.2;H, 6.48; N, 2.67.

EXAMPLE 16

Methyl-(2S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate

Methyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate(3.5 g, 4.8 mmol) was dissolved in 31.5 mL of tetrahydrofuran and 14.4mL of water. A solution of lithium hydroxide (1.022 g, 24 mmol) in 14 mLof water was added over a period of 5 minutes. The reaction mixture washeated to reflux temperature while monitoring the reaction progress byHPLC. After 30 minutes at reflux, HPLC analysis indicated that thereaction contained approximately 28% of the title compound by peak area.Approximately one-half of the reaction mixture (30 mL) was removed andanalyzed by HPLC/MS to identify this --intermediate in the reactionprocess.

HPLC/MS: HPLC conditions--YMCBasic 4.6×150 mm column, solvent system:65:35:0.1, acetonitrile:water:trifluoroacetic acid; flow:1 mL/min, UVdetection at 220 nm. SB 231701, RRT=1.18. MS: m/z 705 (M+H)⁺, 687(M+H-18)⁺, 647 (M+H-58)⁺, 629 (M+H-76)⁺.

EXAMPLE 17

(1S,2R,3S)-2-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5-6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylicacid.

Methyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-a-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate(5.0 g, 0.70 mmol) was dissolved in 45 mL of tetrahydrofuran and 20 mLof methanol. A solution of lithium hydroxide (1.46 g, 3.47 mmol) in 18mL of water was added over a period of 5 minutes. The reaction mixturewas heated to reflux temperature while monitoring the reaction progressby HPLC. After 2 hours at reflux, HPLC analysis indicated that thereaction was complete. The reaction mixture was cooled to 25° C., thendiluted with toluene 40 mL). A 10% solution of citric acid (45 mL) wasadded and the mixture was stirred for five minutes. The layers wereseparated and the aqueous layer was extracted with 40 mL of toluene. Thecombined organic layers were washed twice with 5% sodium bicarbonate 40mL) and filtered. The solution was concentrated under reduced pressureto afford the title compound as a foam as a foam.

¹ H NMR d (CDCl3) 7.30-7.10 (m, 4H), 6.85-6.55 (m, 5H), 6.40 (s, 1H),5.95 (d, 2H), 5.85 (s, 1H), 4.97 (d, 1H), 4.87 (s, 1H), 4.60 (d, 1H),4.40 (m, 1H), 4.00 (m, 4H), 3.80 (m, 2H), 3.80 (m, 3H), 3.15 (m, 1H),1.75 (m. 2H), 1.55 (d, 6H), 2.32 (d, 6H), 1.0 (t, 3H).

EXAMPLE 18

(1S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-[2-hydroxy-4-methoxyphenyl]-5propoxyindane-2-carboxylicacid

Methyl-(1S,2R,3S)-2-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate(0.3183 g, 0.667 mmoles) was dissolved in 2 mL of tetrahydrofuran and 4mL of methanol. A solution of lithium hydroxide (0.1402 g, 3.34 mmoles)in 1.8 mL of water was added over a period in one portion. The reactionmixture was heated to reflux temperature while monitoring the reactionprogress by HPLC. After 22 hours at reflux, HPLC analysis indicated thatthe reaction was complete. The reaction mixture was cooled to 25° C.,then diluted with t-butyl methyl ether (5 mL). A 5% solution of citricacid (5 mL) was added and the mixture was stirred for five minutes. Thelayers were separated and the aqueous layer was extracted with 10 mL oft-butyl methyl ether. The combined organic layers were washed twice withwater and filtered. The solution was concentrated under reduced pressureto afford the title compound as a white solid.

¹ H NMR d (CDCl₃) 7.28 (s, 1H), 7.05 (d, 2H), 6.77 (m, 5H), 6.52 (m,3H), 5.90 (m 2H), 4.87 (d, J=7.5 Hz, 1H), 4.47 (d, J=7.5 Hz, 1H), 3.80(m, 2H), 3.80 (s, 3H), 1.75 (q, J=7 Hz, 2H), 1.0 (t, J=7 Hz, 3H).

EXAMPLE 19

(+)(1S, 2R, 3S)-3-[2-(2-Hydroxyeth-2-yloxy)4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid ethylenediamine salt (2:1)

To 463.0 g (21.7% wt/wt, 203.8 mmol) of a toluene solution ofmethyl-(1S, 2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatewas added 425 mL of toluene, 70 g (496 mmol) of potassium carbonate and183 g (2.04 mol) of ethylene carbonate. The resulting mixture was heatedto approximately 110° C. over a period of 60 minutes then held at thistemperature. The progress of the reaction was monitored by HPLC. Thereaction was considered complete when less than 1.0% PAR (peak arearatio) of starting material was detected. After approximately 3 hours ator around 110° C., the reaction was cooled to 70° C. and DI water (700mL) was added. The mixture was stirred for 15 minutes then the aqueouslayer was separated. The organic layer was washed 5% aqueous citric acidsolution (500 mL) followed by DI water (500 mL). The organic phase wasseparated then concentrated under reduced pressure to a viscous oil. Theconcentrate was diluted with methanol (300 mL) and tetrahydrofuran (500mL) then a solution of lithium hydroxide monohydrate (28 g, 654 mmol)dissolved in 300 mL of deionized water was added. The resulting solutionwas heated to reflux (internal temperature 62-65° C.) over approximately15 minutes and maintained at reflux while monitoring the reactionprogress by HPLC. The reaction was considered complete when nointermediates were detected by in-process HPLC analysis. Afterapproximately 12 hours at reflux the reaction was considered completeand the resulting mixture cooled to ambient temperature. DI water (500mL) was added and the reaction mixture concentrated under reducedpressure to a volume of approximately 1 L. Toluene (760 mL) followed bycitric acid (150 g, 833 mmol) was added to the resulting solution andthe mixture stirred for 5 minutes. The bottom aqueous layer was drainedand the organic layer was washed twice with aqueous brine solution (600mL). The organic layer was separated and filtered to afford 868.8 g of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylicacid as a solution in toluene. HPLC wt/wt assay indicated 11.2% wt/wt(+)(2S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

An analytical sample could be obtained by concentration of the toluenein vacuo and recrystallization from 2-propanol. m.p. 125-127° C. Atoluene solution of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-2-yloxy)indane-2-carboxylicacid (868.8 g@11.2% wt/wt, 192.5 mmol) was concentrated under reducedpressure to a volume of approximately 200 mL. Distillation wasdiscontinued and 2-propanol (500 mL) added to the concentrate. Theorganic solution was concentrated again under reduced pressure to avolume of approximately 200 mL. Distillation was discontinued and2-propanol (500 mL) added to the concentrate. The resulting solution in2-propanol was allowed to stir at ambient temperature for approximately15 minutes to obtain a homogeneous mixture then diluted with anadditional 1000 mL of 2-propanol. The resulting solution was heated toapproximately 60° C. over a period of 15-20 minutes under a gentle purgeof nitrogen. Heating was discontinued and ethylene diamine (11.6 g,99.5+%, 192.5 mmol) was added. The reaction mixture was cooled to 30-35°C. over a period of 4 hours. As the solution cooled to 57° C.,precipitation of the title compound occurred. The resulting slurry wasstirred at ambient temperature for approximately 12 hours then cooled to0° C. an additional 3 hours before isolation of the title compound viafiltration. The product was washed with 3 portions of 2-propanol (300mL) followed by hexane's (600 mL) chilled to 0-5° C. The product wasdried in the vacuum oven for approximately 16 hours at 20-25° C. toafford 91.6 (87%) of the title compound.

Anal Calcd. for C30H34NO8 C, 67.15; H, 6.39; N, 2.61. Found, C, 67.2; H,6.48; N, 2.67.

EXAMPLE 20

Methyl-(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-propoxyindane-2-carboxylate

This intermediate was isolated by flash column chromatography (SiO₂,EtOAc/Hexane=30/70) of a sample of the crude reaction mixture from thepreparation of (1S, 2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylicacid described above prior to the saponification with lithium hydroxide.

¹ H NMR (CDCl₃), d 7.13 (1H, d, J=9 Hz), 6.86-6.71 (5H, m), 6.52-6.45(3H, m), 5.94 (2H, s), 5.02 (1H, s), 4.50 (1H, d, J=12 Hz), 3.99-3.90(3H, m), 3.84-3.75 (4H, m), 3.56 (3H, s). 1.74 92H, qr, J=6 Hz, 15 Hz),0.98 (3H, t, J=6Hz). MS for C₃₀ H₃₂ O₈ : ESI/MS m/z 521(M+1)⁺, 489(M+1-CH₃ OH), 353, 321, 311, 293, 251.

EXAMPLE 21

Preparation of(+)-methyl-(1S,2S,3S)-5-Propoxy-1-(3,4-methylenedioxy-phenyl)-3-(2-carbomethoxy]methoxy-4-methoxyphenyl)indane-2-carboxylate

A 5 L 3 necked round-bottom flask equipped with an air driven stirrer,and a nitrogen inlet/outlet was charged with 212.0 g (98.4% wt/wt, 437.8mmol) ofmethyl-(1S,2S,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate,2120 mL of acetone and 212 mL of methanol. The resulting slurry/solutionwas degassed for approximately 10 minutes under house vacuum. Afterreleasing the vacuum and flushing the flask with nitrogen, 302.5 g (2.19moles) of potassium carbonate followed by 87.1 g (546.6 mmol) of methylbromoacetate were added in single portions. The resulting slurry wasstirred at ambient temperature under an atmosphere of nitrogen while theprogress of the reaction was monitored by HPLC. The reaction was deemedto be complete when all the starting material had been converted to thetitle compound. The slurry was filtered through 300 g of Aluminium oxiderinsing with 1250 mL of acetone. The resulting filtrate was concentratedunder reduced pressure to a volume of approximately 500 mL. Theconcentrate was diluted with 2000 mL of t-butyl methyl ether (TBME) thenwashed with 2×1000 mL portions of 5% aqueous citric acid followed by1000 mL of saturated aqueous brine to afford 1720 g of the titlecompound as a solution in TBME. Analysis indicated 15.6% wt/wt and 98.5%PAR by HPLC. An analytical sample could be obtained by crystallizationof a concentrate from a mixture of hexane's and TBME.

¹ H NMR (CDCl₃), d 7.36 (d, 1H), 7.07 (d, 1H), 6.73-6.88 (m, 5 H), 6.49(q, 1H), 6.37 (d, 1H), 5.94 (s, 2H), 5.17 (d, 1 H), 4.68-4.74 (m, 3 H),4.02 (t, 1H), 3.90 (t, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 2.97 (s, 3H),1.75-1.87 (m, 2H), 1.0 (t, 3H) ppm.

EXAMPLE 22

Preparation of(+)-methyl-(1S,2R,3S)-5-Propoxy-1-(3,4-methylenedioxy-phenyl)-3-(2-[carbomethoxyl]methoxy-4-methoxyphenyl)indane-2-carboxylate

A 1 L 3 necked round-bottom flask equipped with an air driven stirrer,and a nitrogen inlet/outlet was charged with 49.0 g (102.8. mmol) ofmethyl-(1S,2R,3S)-2-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxypheny)-5-propoxyindane-2-carboxylate,490 mL of acetone, 71.0 g of potassium carbonate and 17.3 g (110 mmol)of methyl bromoacetate. The resulting slurry was stirred at ambienttemperature under an atmosphere of nitrogen while the progress of thereaction was monitored by HPLC. The reaction was deemed to be completewhen all the starting material had been converted to the title compound.The slurry was filtered through 50 g of Aluminium oxide rinsing with1250 mL of acetone. The resulting filtrate was concentrated underreduced pressure to a volume of approximately 100 mL. The concentratewas diluted with 500 mL of t-butyl methyl ether then washed with 2×300mL portions of 5% aqueous citric acid followed by drying over anhydrousmagnesium sulphate. The resulting solution was concentrated underreduced pressure to afford 49.2 g of the title compound as an oil. HPLCanalysis indicated 97.8% PAR.

¹ H NMR (CDCl₃) of the crude material, d 7.13 (d, 1H), 6.69-6.82 (m, 5H), 6.48-6.56 (m, 2 H), 6.36 (d, 1H), 5.94 (s, 2H), 4.98 (d, 1H),4.54.65 (m, 3 H), 3.7-3.85 (m, 8 H), 3.6 (s, 3H), 3.33 (t, 1H),1.68-1.80 (m, 2H), 1.0 (t, 3H ) ppm.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that theinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

What is claimed is:
 1. A compound selected from the group consistingof:(1S, 2R, 3S)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylicacid; methyl-(2S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(2-(2,3:5,6-di-O-isopropylidene)-.alpha.-D-mannofuranosyloxy-4-methoxyphenyl)-5-propoxyindane-2-carboxylate:methyl-(1R, 2R,3R)-1-(3,4-methylenedioxyphenyl)-3-[2-(2,3:5,6-di-O-isopropylidene)-.alpha.-D-mannofuranosyloxy-4-methoxyphenyl]-5-propoxyindane-2-carboxylate;methyl-(1S,2S,3S)-2-(3,4-methylenedioxyphenyl)3-[2-(2,3:5,6-di-O-isopropylidene)-α-D-mannofuranosyloxyloxy-4-methoxyphenyl]-5-propoxy-indane-2-carboxylate;(S)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-(2-(2,3:5,6-isopropylidene)-α-D-mannofuranosyloxy-4-methoxyphenyl-6-propoxy-1H-indene-2-carboxylate;(R)-methyl-3-(3,4-methylenedioxyphenyl)-1-hydroxy-1-(2-(2,3:5,6-isopropylidene)-α-D-mannofuranosyloxy-4-methoxyphenyl)-6-propoxy-1H-indene-2-carboxylate;2,6-Dimethyl-4-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyloxy)bromobenzene,2-Bromo-5-methoxyphenyl 2,3:5,6-di-O-isopropylidene-α-D-mannofuranoside;or2-Bromo-5-methoxyphenyl-2,3:5,6-di-O-isopropylidene-β-D-mannofuranoside.